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  • Models, Molecular  (174)
  • Cells, Cultured  (103)
  • Astronomy
  • Chemistry
  • Condensed Matter: Electronic Properties, etc.
  • Nature Publishing Group (NPG)  (274)
  • 2010-2014  (274)
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  • 1
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    A promoter-level mammalian expression atlas (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-03-29
    Description: Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529748/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529748/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉FANTOM Consortium and the RIKEN PMI and CLST (DGT) -- Forrest, Alistair R R -- Kawaji, Hideya -- Rehli, Michael -- Baillie, J Kenneth -- de Hoon, Michiel J L -- Haberle, Vanja -- Lassmann, Timo -- Kulakovskiy, Ivan V -- Lizio, Marina -- Itoh, Masayoshi -- Andersson, Robin -- Mungall, Christopher J -- Meehan, Terrence F -- Schmeier, Sebastian -- Bertin, Nicolas -- Jorgensen, Mette -- Dimont, Emmanuel -- Arner, Erik -- Schmidl, Christian -- Schaefer, Ulf -- Medvedeva, Yulia A -- Plessy, Charles -- Vitezic, Morana -- Severin, Jessica -- Semple, Colin A -- Ishizu, Yuri -- Young, Robert S -- Francescatto, Margherita -- Alam, Intikhab -- Albanese, Davide -- Altschuler, Gabriel M -- Arakawa, Takahiro -- Archer, John A C -- Arner, Peter -- Babina, Magda -- Rennie, Sarah -- Balwierz, Piotr J -- Beckhouse, Anthony G -- Pradhan-Bhatt, Swati -- Blake, Judith A -- Blumenthal, Antje -- Bodega, Beatrice -- Bonetti, Alessandro -- Briggs, James -- Brombacher, Frank -- Burroughs, A Maxwell -- Califano, Andrea -- Cannistraci, Carlo V -- Carbajo, Daniel -- Chen, Yun -- Chierici, Marco -- Ciani, Yari -- Clevers, Hans C -- Dalla, Emiliano -- Davis, Carrie A -- Detmar, Michael -- Diehl, Alexander D -- Dohi, Taeko -- Drablos, Finn -- Edge, Albert S B -- Edinger, Matthias -- Ekwall, Karl -- Endoh, Mitsuhiro -- Enomoto, Hideki -- Fagiolini, Michela -- Fairbairn, Lynsey -- Fang, Hai -- Farach-Carson, Mary C -- Faulkner, Geoffrey J -- Favorov, Alexander V -- Fisher, Malcolm E -- Frith, Martin C -- Fujita, Rie -- Fukuda, Shiro -- Furlanello, Cesare -- Furino, Masaaki -- Furusawa, Jun-ichi -- Geijtenbeek, Teunis B -- Gibson, Andrew P -- Gingeras, Thomas -- Goldowitz, Daniel -- Gough, Julian -- Guhl, Sven -- Guler, Reto -- Gustincich, Stefano -- Ha, Thomas J -- Hamaguchi, Masahide -- Hara, Mitsuko -- Harbers, Matthias -- Harshbarger, Jayson -- Hasegawa, Akira -- Hasegawa, Yuki -- Hashimoto, Takehiro -- Herlyn, Meenhard -- Hitchens, Kelly J -- Ho Sui, Shannan J -- Hofmann, Oliver M -- Hoof, Ilka -- Hori, Furni -- Huminiecki, Lukasz -- Iida, Kei -- Ikawa, Tomokatsu -- Jankovic, Boris R -- Jia, Hui -- Joshi, Anagha -- Jurman, Giuseppe -- Kaczkowski, Bogumil -- Kai, Chieko -- Kaida, Kaoru -- Kaiho, Ai -- Kajiyama, Kazuhiro -- Kanamori-Katayama, Mutsumi -- Kasianov, Artem S -- Kasukawa, Takeya -- Katayama, Shintaro -- Kato, Sachi -- Kawaguchi, Shuji -- Kawamoto, Hiroshi -- Kawamura, Yuki I -- Kawashima, Tsugumi -- Kempfle, Judith S -- Kenna, Tony J -- Kere, Juha -- Khachigian, Levon M -- Kitamura, Toshio -- Klinken, S Peter -- Knox, Alan J -- Kojima, Miki -- Kojima, Soichi -- Kondo, Naoto -- Koseki, Haruhiko -- Koyasu, Shigeo -- Krampitz, Sarah -- Kubosaki, Atsutaka -- Kwon, Andrew T -- Laros, Jeroen F J -- Lee, Weonju -- Lennartsson, Andreas -- Li, Kang -- Lilje, Berit -- Lipovich, Leonard -- Mackay-Sim, Alan -- Manabe, Ri-ichiroh -- Mar, Jessica C -- Marchand, Benoit -- Mathelier, Anthony -- Mejhert, Niklas -- Meynert, Alison -- Mizuno, Yosuke -- de Lima Morais, David A -- Morikawa, Hiromasa -- Morimoto, Mitsuru -- Moro, Kazuyo -- Motakis, Efthymios -- Motohashi, Hozumi -- Mummery, Christine L -- Murata, Mitsuyoshi -- Nagao-Sato, Sayaka -- Nakachi, Yutaka -- Nakahara, Fumio -- Nakamura, Toshiyuki -- Nakamura, Yukio -- Nakazato, Kenichi -- van Nimwegen, Erik -- Ninomiya, Noriko -- Nishiyori, Hiromi -- Noma, Shohei -- Noazaki, Tadasuke -- Ogishima, Soichi -- Ohkura, Naganari -- Ohimiya, Hiroko -- Ohno, Hiroshi -- Ohshima, Mitsuhiro -- Okada-Hatakeyama, Mariko -- Okazaki, Yasushi -- Orlando, Valerio -- Ovchinnikov, Dmitry A -- Pain, Arnab -- Passier, Robert -- Patrikakis, Margaret -- Persson, Helena -- Piazza, Silvano -- Prendergast, James G D -- Rackham, Owen J L -- Ramilowski, Jordan A -- Rashid, Mamoon -- Ravasi, Timothy -- Rizzu, Patrizia -- Roncador, Marco -- Roy, Sugata -- Rye, Morten B -- Saijyo, Eri -- Sajantila, Antti -- Saka, Akiko -- Sakaguchi, Shimon -- Sakai, Mizuho -- Sato, Hiroki -- Savvi, Suzana -- Saxena, Alka -- Schneider, Claudio -- Schultes, Erik A -- Schulze-Tanzil, Gundula G -- Schwegmann, Anita -- Sengstag, Thierry -- Sheng, Guojun -- Shimoji, Hisashi -- Shimoni, Yishai -- Shin, Jay W -- Simon, Christophe -- Sugiyama, Daisuke -- Sugiyama, Takaai -- Suzuki, Masanori -- Suzuki, Naoko -- Swoboda, Rolf K -- 't Hoen, Peter A C -- Tagami, Michihira -- Takahashi, Naoko -- Takai, Jun -- Tanaka, Hiroshi -- Tatsukawa, Hideki -- Tatum, Zuotian -- Thompson, Mark -- Toyodo, Hiroo -- Toyoda, Tetsuro -- Valen, Elvind -- van de Wetering, Marc -- van den Berg, Linda M -- Verado, Roberto -- Vijayan, Dipti -- Vorontsov, Ilya E -- Wasserman, Wyeth W -- Watanabe, Shoko -- Wells, Christine A -- Winteringham, Louise N -- Wolvetang, Ernst -- Wood, Emily J -- Yamaguchi, Yoko -- Yamamoto, Masayuki -- Yoneda, Misako -- Yonekura, Yohei -- Yoshida, Shigehiro -- Zabierowski, Susan E -- Zhang, Peter G -- Zhao, Xiaobei -- Zucchelli, Silvia -- Summers, Kim M -- Suzuki, Harukazu -- Daub, Carsten O -- Kawai, Jun -- Heutink, Peter -- Hide, Winston -- Freeman, Tom C -- Lenhard, Boris -- Bajic, Vladimir B -- Taylor, Martin S -- Makeev, Vsevolod J -- Sandelin, Albin -- Hume, David A -- Carninci, Piero -- Hayashizaki, Yoshihide -- BB/F003722/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G022771/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/I001107/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_PC_U127597124/Medical Research Council/United Kingdom -- MC_UP_1102/1/Medical Research Council/United Kingdom -- R01 DE022969/DE/NIDCR NIH HHS/ -- R01 GM084875/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Mar 27;507(7493):462-70. doi: 10.1038/nature13182.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670764" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Atlases as Topic ; Cell Line ; Cells, Cultured ; Cluster Analysis ; Conserved Sequence/genetics ; Gene Expression Regulation/genetics ; Gene Regulatory Networks/genetics ; Genes, Essential/genetics ; Genome/genetics ; Humans ; Mice ; *Molecular Sequence Annotation ; Open Reading Frames/genetics ; Organ Specificity ; Promoter Regions, Genetic/*genetics ; RNA, Messenger/analysis/genetics ; Transcription Factors/metabolism ; Transcription Initiation Site ; Transcription, Genetic/genetics ; Transcriptome/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-04-04
    Description: Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gad, Helge -- Koolmeister, Tobias -- Jemth, Ann-Sofie -- Eshtad, Saeed -- Jacques, Sylvain A -- Strom, Cecilia E -- Svensson, Linda M -- Schultz, Niklas -- Lundback, Thomas -- Einarsdottir, Berglind Osk -- Saleh, Aljona -- Gokturk, Camilla -- Baranczewski, Pawel -- Svensson, Richard -- Berntsson, Ronnie P-A -- Gustafsson, Robert -- Stromberg, Kia -- Sanjiv, Kumar -- Jacques-Cordonnier, Marie-Caroline -- Desroses, Matthieu -- Gustavsson, Anna-Lena -- Olofsson, Roger -- Johansson, Fredrik -- Homan, Evert J -- Loseva, Olga -- Brautigam, Lars -- Johansson, Lars -- Hoglund, Andreas -- Hagenkort, Anna -- Pham, Therese -- Altun, Mikael -- Gaugaz, Fabienne Z -- Vikingsson, Svante -- Evers, Bastiaan -- Henriksson, Martin -- Vallin, Karl S A -- Wallner, Olov A -- Hammarstrom, Lars G J -- Wiita, Elisee -- Almlof, Ingrid -- Kalderen, Christina -- Axelsson, Hanna -- Djureinovic, Tatjana -- Puigvert, Jordi Carreras -- Haggblad, Maria -- Jeppsson, Fredrik -- Martens, Ulf -- Lundin, Cecilia -- Lundgren, Bo -- Granelli, Ingrid -- Jensen, Annika Jenmalm -- Artursson, Per -- Nilsson, Jonas A -- Stenmark, Pal -- Scobie, Martin -- Berglund, Ulrika Warpman -- Helleday, Thomas -- England -- Nature. 2014 Apr 10;508(7495):215-21. doi: 10.1038/nature13181. Epub 2014 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2]. ; Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden. ; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. ; Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, Department of Surgery, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden. ; Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden. ; 1] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden. ; Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Clinical Pharmacology, Department of Medical and Health Sciences, Linkoping University, S-58185 Linkoping, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.). ; 1] Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden [2] Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.). ; Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695224" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Catalytic Domain ; Cell Death/drug effects ; Cell Survival/drug effects ; Crystallization ; DNA Damage ; DNA Repair Enzymes/*antagonists & inhibitors/chemistry/metabolism ; Deoxyguanine Nucleotides/metabolism ; Enzyme Inhibitors/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Female ; Humans ; Male ; Mice ; Models, Molecular ; Molecular Conformation ; Molecular Targeted Therapy ; Neoplasms/*drug therapy/*metabolism/pathology ; Nucleotides/*metabolism ; Oxidation-Reduction/drug effects ; Phosphoric Monoester Hydrolases/*antagonists & inhibitors/chemistry/metabolism ; Pyrimidines/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Pyrophosphatases/antagonists & inhibitors ; Reproducibility of Results ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Femtosecond X-ray protein nanocrystallography (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-02-05
    Description: X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded. It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source. We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes. More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals ( approximately 200 nm to 2 mum in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes. This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429598/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429598/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chapman, Henry N -- Fromme, Petra -- Barty, Anton -- White, Thomas A -- Kirian, Richard A -- Aquila, Andrew -- Hunter, Mark S -- Schulz, Joachim -- DePonte, Daniel P -- Weierstall, Uwe -- Doak, R Bruce -- Maia, Filipe R N C -- Martin, Andrew V -- Schlichting, Ilme -- Lomb, Lukas -- Coppola, Nicola -- Shoeman, Robert L -- Epp, Sascha W -- Hartmann, Robert -- Rolles, Daniel -- Rudenko, Artem -- Foucar, Lutz -- Kimmel, Nils -- Weidenspointner, Georg -- Holl, Peter -- Liang, Mengning -- Barthelmess, Miriam -- Caleman, Carl -- Boutet, Sebastien -- Bogan, Michael J -- Krzywinski, Jacek -- Bostedt, Christoph -- Bajt, Sasa -- Gumprecht, Lars -- Rudek, Benedikt -- Erk, Benjamin -- Schmidt, Carlo -- Homke, Andre -- Reich, Christian -- Pietschner, Daniel -- Struder, Lothar -- Hauser, Gunter -- Gorke, Hubert -- Ullrich, Joachim -- Herrmann, Sven -- Schaller, Gerhard -- Schopper, Florian -- Soltau, Heike -- Kuhnel, Kai-Uwe -- Messerschmidt, Marc -- Bozek, John D -- Hau-Riege, Stefan P -- Frank, Matthias -- Hampton, Christina Y -- Sierra, Raymond G -- Starodub, Dmitri -- Williams, Garth J -- Hajdu, Janos -- Timneanu, Nicusor -- Seibert, M Marvin -- Andreasson, Jakob -- Rocker, Andrea -- Jonsson, Olof -- Svenda, Martin -- Stern, Stephan -- Nass, Karol -- Andritschke, Robert -- Schroter, Claus-Dieter -- Krasniqi, Faton -- Bott, Mario -- Schmidt, Kevin E -- Wang, Xiaoyu -- Grotjohann, Ingo -- Holton, James M -- Barends, Thomas R M -- Neutze, Richard -- Marchesini, Stefano -- Fromme, Raimund -- Schorb, Sebastian -- Rupp, Daniela -- Adolph, Marcus -- Gorkhover, Tais -- Andersson, Inger -- Hirsemann, Helmut -- Potdevin, Guillaume -- Graafsma, Heinz -- Nilsson, Bjorn -- Spence, John C H -- 1R01GM095583-01/GM/NIGMS NIH HHS/ -- 1U54GM094625-01/GM/NIGMS NIH HHS/ -- R01 GM095583/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Feb 3;470(7332):73-7. doi: 10.1038/nature09750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany. henry.chapman@desy.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21293373" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray/instrumentation/*methods ; Lasers ; Models, Molecular ; Nanoparticles/*chemistry ; Nanotechnology/instrumentation/*methods ; Photosystem I Protein Complex/*chemistry ; Protein Conformation ; Time Factors ; X-Rays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-11-15
    Description: Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic beta-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lloyd, David J -- St Jean, David J Jr -- Kurzeja, Robert J M -- Wahl, Robert C -- Michelsen, Klaus -- Cupples, Rod -- Chen, Michelle -- Wu, John -- Sivits, Glenn -- Helmering, Joan -- Komorowski, Renee -- Ashton, Kate S -- Pennington, Lewis D -- Fotsch, Christopher -- Vazir, Mukta -- Chen, Kui -- Chmait, Samer -- Zhang, Jiandong -- Liu, Longbin -- Norman, Mark H -- Andrews, Kristin L -- Bartberger, Michael D -- Van, Gwyneth -- Galbreath, Elizabeth J -- Vonderfecht, Steven L -- Wang, Minghan -- Jordan, Steven R -- Veniant, Murielle M -- Hale, Clarence -- England -- Nature. 2013 Dec 19;504(7480):437-40. doi: 10.1038/nature12724. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Comparative Biology & Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226772" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Blood Glucose/metabolism ; Carrier Proteins/*antagonists & inhibitors/metabolism ; Cell Nucleus/enzymology ; Crystallography, X-Ray ; Diabetes Mellitus, Type 2/blood/*drug therapy/enzymology ; Disease Models, Animal ; Hepatocytes ; Humans ; Hyperglycemia/blood/drug therapy/enzymology ; Hypoglycemic Agents/chemistry/*pharmacology/*therapeutic use ; Liver/cytology/enzymology/metabolism ; Male ; Models, Molecular ; Organ Specificity ; Phosphorylation/drug effects ; Piperazines/chemistry/metabolism/pharmacology/therapeutic use ; Protein Binding/drug effects ; Protein Transport/drug effects ; Rats ; Rats, Wistar ; Sulfonamides/chemistry/metabolism/pharmacology/therapeutic use
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Targeting Plasmodium PI(4)K to eliminate malaria (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-29
    Description: Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940870/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McNamara, Case W -- Lee, Marcus C S -- Lim, Chek Shik -- Lim, Siau Hoi -- Roland, Jason -- Nagle, Advait -- Simon, Oliver -- Yeung, Bryan K S -- Chatterjee, Arnab K -- McCormack, Susan L -- Manary, Micah J -- Zeeman, Anne-Marie -- Dechering, Koen J -- Kumar, T R Santha -- Henrich, Philipp P -- Gagaring, Kerstin -- Ibanez, Maureen -- Kato, Nobutaka -- Kuhen, Kelli L -- Fischli, Christoph -- Rottmann, Matthias -- Plouffe, David M -- Bursulaya, Badry -- Meister, Stephan -- Rameh, Lucia -- Trappe, Joerg -- Haasen, Dorothea -- Timmerman, Martijn -- Sauerwein, Robert W -- Suwanarusk, Rossarin -- Russell, Bruce -- Renia, Laurent -- Nosten, Francois -- Tully, David C -- Kocken, Clemens H M -- Glynne, Richard J -- Bodenreider, Christophe -- Fidock, David A -- Diagana, Thierry T -- Winzeler, Elizabeth A -- 078285/Wellcome Trust/United Kingdom -- 089275/Wellcome Trust/United Kingdom -- 090534/Wellcome Trust/United Kingdom -- 096157/Wellcome Trust/United Kingdom -- R01 AI079709/AI/NIAID NIH HHS/ -- R01 AI085584/AI/NIAID NIH HHS/ -- R01 AI090141/AI/NIAID NIH HHS/ -- R01 AI103058/AI/NIAID NIH HHS/ -- R01079709/PHS HHS/ -- R01085584/PHS HHS/ -- R01AI090141/AI/NIAID NIH HHS/ -- WT078285/Wellcome Trust/United Kingdom -- WT096157/Wellcome Trust/United Kingdom -- England -- Nature. 2013 Dec 12;504(7479):248-53. doi: 10.1038/nature12782. Epub 2013 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA [2]. ; 1] Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA [2]. ; Novartis Institutes for Tropical Disease, 138670 Singapore. ; Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA. ; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; Department of Parasitology, Biomedical Primate Research Centre, PO Box 3306, 2280 GH Rijswijk, The Netherlands. ; TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands. ; Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA. ; Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland. ; 1] Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland [2] University of Basel, CH-4003 Basel, Switzerland. ; Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts 02118, USA. ; Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. ; 1] TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands [2] Department of Medical Microbiology, Radboud University, Nijmegen Medical CentrePO Box 9101, 6500 HB Nijmegen, The Netherlands. ; Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore. ; 1] Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore [2] Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 117545 Singapore. ; 1] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK [2] Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot 63110, Thailand. ; 1] Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA [2] Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA. ; 1] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA [2] Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24284631" target="_blank"〉PubMed〈/a〉
    Keywords: 1-Phosphatidylinositol 4-Kinase/*antagonists & ; inhibitors/chemistry/genetics/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; Cytokinesis/drug effects ; Drug Resistance/drug effects/genetics ; Fatty Acids/metabolism ; Female ; Hepatocytes/parasitology ; Humans ; Imidazoles/metabolism/pharmacology ; Life Cycle Stages/drug effects ; Macaca mulatta ; Malaria/*drug therapy/*parasitology ; Male ; Models, Biological ; Models, Molecular ; Phosphatidylinositol Phosphates/metabolism ; Plasmodium/classification/*drug effects/*enzymology/growth & development ; Pyrazoles/metabolism/pharmacology ; Quinoxalines/metabolism/pharmacology ; Reproducibility of Results ; Schizonts/cytology/drug effects ; rab GTP-Binding Proteins/genetics/metabolism
    Print ISSN: 0028-0836
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    Initial genome sequencing and analysis of multiple myeloma (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-03-25
    Description: Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-kappaB signalling was indicated by mutations in 11 members of the NF-kappaB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560292/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560292/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chapman, Michael A -- Lawrence, Michael S -- Keats, Jonathan J -- Cibulskis, Kristian -- Sougnez, Carrie -- Schinzel, Anna C -- Harview, Christina L -- Brunet, Jean-Philippe -- Ahmann, Gregory J -- Adli, Mazhar -- Anderson, Kenneth C -- Ardlie, Kristin G -- Auclair, Daniel -- Baker, Angela -- Bergsagel, P Leif -- Bernstein, Bradley E -- Drier, Yotam -- Fonseca, Rafael -- Gabriel, Stacey B -- Hofmeister, Craig C -- Jagannath, Sundar -- Jakubowiak, Andrzej J -- Krishnan, Amrita -- Levy, Joan -- Liefeld, Ted -- Lonial, Sagar -- Mahan, Scott -- Mfuko, Bunmi -- Monti, Stefano -- Perkins, Louise M -- Onofrio, Robb -- Pugh, Trevor J -- Rajkumar, S Vincent -- Ramos, Alex H -- Siegel, David S -- Sivachenko, Andrey -- Stewart, A Keith -- Trudel, Suzanne -- Vij, Ravi -- Voet, Douglas -- Winckler, Wendy -- Zimmerman, Todd -- Carpten, John -- Trent, Jeff -- Hahn, William C -- Garraway, Levi A -- Meyerson, Matthew -- Lander, Eric S -- Getz, Gad -- Golub, Todd R -- K12 CA133250/CA/NCI NIH HHS/ -- R01 AG020686/AG/NIA NIH HHS/ -- R01 AG020686-07/AG/NIA NIH HHS/ -- R01 CA133115/CA/NCI NIH HHS/ -- R01 CA133115-04/CA/NCI NIH HHS/ -- R01 CA133966/CA/NCI NIH HHS/ -- R01 CA133966-03/CA/NCI NIH HHS/ -- England -- Nature. 2011 Mar 24;471(7339):467-72. doi: 10.1038/nature09837.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02412, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430775" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Blood Coagulation/genetics ; CpG Islands/genetics ; DNA Mutational Analysis ; DNA Repair/genetics ; Exons/genetics ; Exosome Multienzyme Ribonuclease Complex ; Genome, Human/*genetics ; Genomics ; Histones/metabolism ; Homeodomain Proteins/genetics ; Homeostasis/genetics ; Humans ; Methylation ; Models, Molecular ; Molecular Sequence Data ; Multiple Myeloma/drug therapy/enzymology/*genetics/metabolism ; Mutation/*genetics ; NF-kappa B/metabolism ; Oncogenes/genetics ; Open Reading Frames/genetics ; Protein Biosynthesis/genetics ; Protein Conformation ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics/metabolism ; RNA Processing, Post-Transcriptional/genetics ; Ribonucleases/chemistry/genetics ; Signal Transduction/genetics ; Transcription, Genetic/genetics
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    MR1 presents microbial vitamin B metabolites to MAIT cells (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-12
    Description: Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kjer-Nielsen, Lars -- Patel, Onisha -- Corbett, Alexandra J -- Le Nours, Jerome -- Meehan, Bronwyn -- Liu, Ligong -- Bhati, Mugdha -- Chen, Zhenjun -- Kostenko, Lyudmila -- Reantragoon, Rangsima -- Williamson, Nicholas A -- Purcell, Anthony W -- Dudek, Nadine L -- McConville, Malcolm J -- O'Hair, Richard A J -- Khairallah, George N -- Godfrey, Dale I -- Fairlie, David P -- Rossjohn, Jamie -- McCluskey, James -- England -- Nature. 2012 Nov 29;491(7426):717-23. doi: 10.1038/nature11605. Epub 2012 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23051753" target="_blank"〉PubMed〈/a〉
    Keywords: Antigen Presentation ; Bacterial Infections/immunology/microbiology ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Folic Acid/chemistry/immunology/*metabolism ; Histocompatibility Antigens/chemistry/immunology ; Histocompatibility Antigens Class I/*chemistry/*immunology/metabolism ; Humans ; Immunologic Surveillance/immunology ; Jurkat Cells ; Ligands ; Lymphocyte Activation ; Models, Molecular ; Protein Refolding/drug effects ; Pterins/*chemistry/*immunology/metabolism/pharmacology ; Salmonella/immunology/metabolism ; Salmonella Infections/immunology/microbiology ; Static Electricity ; T-Lymphocytes/*immunology ; beta 2-Microglobulin/immunology/metabolism
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    Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells (2012)
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    Publication Date: 2012-10-30
    Description: In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE). We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-beta (IFN-beta) and/or IFN-lambda1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-beta and IFN-lambda1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-alpha or IFN-beta ( IFN-alpha/beta) but not IFN-lambda1. Thus, impaired TLR3- and UNC-93B-dependent IFN-alpha/beta intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527075/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527075/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lafaille, Fabien G -- Pessach, Itai M -- Zhang, Shen-Ying -- Ciancanelli, Michael J -- Herman, Melina -- Abhyankar, Avinash -- Ying, Shui-Wang -- Keros, Sotirios -- Goldstein, Peter A -- Mostoslavsky, Gustavo -- Ordovas-Montanes, Jose -- Jouanguy, Emmanuelle -- Plancoulaine, Sabine -- Tu, Edmund -- Elkabetz, Yechiel -- Al-Muhsen, Saleh -- Tardieu, Marc -- Schlaeger, Thorsten M -- Daley, George Q -- Abel, Laurent -- Casanova, Jean-Laurent -- Studer, Lorenz -- Notarangelo, Luigi D -- 1R01NS066390/NS/NINDS NIH HHS/ -- 1R03AI0883502-01/AI/NIAID NIH HHS/ -- 5R01NS072381-02/NS/NINDS NIH HHS/ -- 8UL1TR000043/TR/NCATS NIH HHS/ -- K12 NS066274/NS/NINDS NIH HHS/ -- R01 NS066390/NS/NINDS NIH HHS/ -- R01 NS072381/NS/NINDS NIH HHS/ -- R03 AI088352/AI/NIAID NIH HHS/ -- UL1 TR000043/TR/NCATS NIH HHS/ -- England -- Nature. 2012 Nov 29;491(7426):769-73. doi: 10.1038/nature11583. Epub 2012 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103873" target="_blank"〉PubMed〈/a〉
    Keywords: Astrocytes/immunology/virology ; Biomarkers ; Cell Differentiation ; Cell Lineage ; Cell Separation ; Cells, Cultured ; Central Nervous System/cytology/immunology/*pathology/virology ; Child ; Disease Susceptibility ; Encephalitis, Herpes Simplex/immunology/metabolism/pathology/virology ; Herpesvirus 1, Human/*immunology/pathogenicity ; Humans ; Immunity, Innate ; Induced Pluripotent Stem Cells/*cytology/virology ; Interferons/immunology ; Membrane Transport Proteins/deficiency/genetics ; Neural Stem Cells/immunology/virology ; Neurons/immunology/pathology/virology ; Oligodendroglia/immunology/pathology/virology ; Toll-Like Receptor 3/*deficiency/genetics
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    A Ctf4 trimer couples the CMG helicase to DNA polymerase alpha in the eukaryotic replisome (2014)
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    Publication Date: 2014-05-09
    Description: Efficient duplication of the genome requires the concerted action of helicase and DNA polymerases at replication forks to avoid stalling of the replication machinery and consequent genomic instability. In eukaryotes, the physical coupling between helicase and DNA polymerases remains poorly understood. Here we define the molecular mechanism by which the yeast Ctf4 protein links the Cdc45-MCM-GINS (CMG) DNA helicase to DNA polymerase alpha (Pol alpha) within the replisome. We use X-ray crystallography and electron microscopy to show that Ctf4 self-associates in a constitutive disk-shaped trimer. Trimerization depends on a beta-propeller domain in the carboxy-terminal half of the protein, which is fused to a helical extension that protrudes from one face of the trimeric disk. Critically, Pol alpha and the CMG helicase share a common mechanism of interaction with Ctf4. We show that the amino-terminal tails of the catalytic subunit of Pol alpha and the Sld5 subunit of GINS contain a conserved Ctf4-binding motif that docks onto the exposed helical extension of a Ctf4 protomer within the trimer. Accordingly, we demonstrate that one Ctf4 trimer can support binding of up to three partner proteins, including the simultaneous association with both Pol alpha and GINS. Our findings indicate that Ctf4 can couple two molecules of Pol alpha to one CMG helicase within the replisome, providing a new model for lagging-strand synthesis in eukaryotes that resembles the emerging model for the simpler replisome of Escherichia coli. The ability of Ctf4 to act as a platform for multivalent interactions illustrates a mechanism for the concurrent recruitment of factors that act together at the fork.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059944/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simon, Aline C -- Zhou, Jin C -- Perera, Rajika L -- van Deursen, Frederick -- Evrin, Cecile -- Ivanova, Marina E -- Kilkenny, Mairi L -- Renault, Ludovic -- Kjaer, Svend -- Matak-Vinkovic, Dijana -- Labib, Karim -- Costa, Alessandro -- Pellegrini, Luca -- 084279/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Jun 12;510(7504):293-7. doi: 10.1038/nature13234. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [2]. ; 1] Clare Hall Laboratories, Cancer Research UK London Research Institute, London EN6 3LD, UK [2]. ; 1] Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK [2] Imperial College, South Kensington, London SW7 2AZ, UK (R.L.P.); Cancer Research UK London Research Institute, London WC2A 3LY, UK (M.E.I.). ; Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK. ; MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. ; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK. ; Clare Hall Laboratories, Cancer Research UK London Research Institute, London EN6 3LD, UK. ; Protein purification, Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805245" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; DNA Helicases/chemistry/*metabolism/ultrastructure ; DNA Polymerase I/chemistry/*metabolism/ultrastructure ; *DNA Replication ; DNA-Binding Proteins/*chemistry/*metabolism/ultrastructure ; DNA-Directed DNA Polymerase/*chemistry/*metabolism ; Microscopy, Electron ; Minichromosome Maintenance Proteins/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Multienzyme Complexes/*chemistry/*metabolism ; Nuclear Proteins/chemistry/metabolism ; Protein Binding ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Saccharomyces cerevisiae/*chemistry/ultrastructure ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism/ultrastructure
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    Light-avoidance-mediating photoreceptors tile the Drosophila larval body wall (2010)
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    Publication Date: 2010-11-12
    Description: Photoreceptors for visual perception, phototaxis or light avoidance are typically clustered in eyes or related structures such as the Bolwig organ of Drosophila larvae. Unexpectedly, we found that the class IV dendritic arborization neurons of Drosophila melanogaster larvae respond to ultraviolet, violet and blue light, and are major mediators of light avoidance, particularly at high intensities. These class IV dendritic arborization neurons, which are present in every body segment, have dendrites tiling the larval body wall nearly completely without redundancy. Dendritic illumination activates class IV dendritic arborization neurons. These novel photoreceptors use phototransduction machinery distinct from other photoreceptors in Drosophila and enable larvae to sense light exposure over their entire bodies and move out of danger.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026603/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026603/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiang, Yang -- Yuan, Quan -- Vogt, Nina -- Looger, Loren L -- Jan, Lily Yeh -- Jan, Yuh Nung -- R01 MH084234/MH/NIMH NIH HHS/ -- R37 NS040929/NS/NINDS NIH HHS/ -- R37 NS040929-11/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Dec 16;468(7326):921-6. doi: 10.1038/nature09576. Epub 2010 Nov 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Departments of Physiology, Biochemistry, and Biophysics, University of California San Francisco, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21068723" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Structures/cytology/metabolism/radiation effects ; Animals ; Avoidance Learning/physiology/radiation effects ; Cells, Cultured ; Dermis/metabolism/radiation effects ; Drosophila Proteins/metabolism ; Drosophila melanogaster/*anatomy & histology/cytology/physiology/*radiation ; effects ; Larva/anatomy & histology/cytology/radiation effects ; *Light ; Light Signal Transduction/radiation effects ; Neurons/physiology/radiation effects ; Photoreceptor Cells, Invertebrate/*metabolism/*radiation effects ; Receptors, Cell Surface/metabolism ; TRPC Cation Channels/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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