ALBERT

Description: People exert large amounts of problem-solving effort playing computer games. Simple image- and text-recognition tasks have been successfully 'crowd-sourced' through games, but it is not clear if more complex scientific problems can be solved with human-directed computing. Protein structure prediction is one such problem: locating the biologically relevant native conformation of a protein is a formidable computational challenge given the very large size of the search space. Here we describe Foldit, a multiplayer online game that engages non-scientists in solving hard prediction problems. Foldit players interact with protein structures using direct manipulation tools and user-friendly versions of algorithms from the Rosetta structure prediction methodology, while they compete and collaborate to optimize the computed energy. We show that top-ranked Foldit players excel at solving challenging structure refinement problems in which substantial backbone rearrangements are necessary to achieve the burial of hydrophobic residues. Players working collaboratively develop a rich assortment of new strategies and algorithms; unlike computational approaches, they explore not only the conformational space but also the space of possible search strategies. The integration of human visual problem-solving and strategy development capabilities with traditional computational algorithms through interactive multiplayer games is a powerful new approach to solving computationally-limited scientific problems.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956414/" 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/PMC2956414/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cooper, Seth -- Khatib, Firas -- Treuille, Adrien -- Barbero, Janos -- Lee, Jeehyung -- Beenen, Michael -- Leaver-Fay, Andrew -- Baker, David -- Popovic, Zoran -- Players, Foldit -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Aug 5;466(7307):756-60. doi: 10.1038/nature09304.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computer Science and Engineering, University of Washington, Box 352350, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20686574" target="_blank"〉PubMed〈/a〉

Description: Group II chaperonins are essential mediators of cellular protein folding in eukaryotes and archaea. These oligomeric protein machines, approximately 1 megadalton, consist of two back-to-back rings encompassing a central cavity that accommodates polypeptide substrates. Chaperonin-mediated protein folding is critically dependent on the closure of a built-in lid, which is triggered by ATP hydrolysis. The structural rearrangements and molecular events leading to lid closure are still unknown. Here we report four single particle cryo-electron microscopy (cryo-EM) structures of Mm-cpn, an archaeal group II chaperonin, in the nucleotide-free (open) and nucleotide-induced (closed) states. The 4.3 A resolution of the closed conformation allowed building of the first ever atomic model directly from the single particle cryo-EM density map, in which we were able to visualize the nucleotide and more than 70% of the side chains. The model of the open conformation was obtained by using the deformable elastic network modelling with the 8 A resolution open-state cryo-EM density restraints. Together, the open and closed structures show how local conformational changes triggered by ATP hydrolysis lead to an alteration of intersubunit contacts within and across the rings, ultimately causing a rocking motion that closes the ring. Our analyses show that there is an intricate and unforeseen set of interactions controlling allosteric communication and inter-ring signalling, driving the conformational cycle of group II chaperonins. Beyond this, we anticipate that our methodology of combining single particle cryo-EM and computational modelling will become a powerful tool in the determination of atomic details involved in the dynamic processes of macromolecular machines in solution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834796/" 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/PMC2834796/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Junjie -- Baker, Matthew L -- Schroder, Gunnar F -- Douglas, Nicholai R -- Reissmann, Stefanie -- Jakana, Joanita -- Dougherty, Matthew -- Fu, Caroline J -- Levitt, Michael -- Ludtke, Steven J -- Frydman, Judith -- Chiu, Wah -- P41 RR002250/RR/NCRR NIH HHS/ -- P41 RR002250-23/RR/NCRR NIH HHS/ -- P41 RR002250-237254/RR/NCRR NIH HHS/ -- P41 RR002250-24/RR/NCRR NIH HHS/ -- P41 RR002250-247897/RR/NCRR NIH HHS/ -- PN2 EY016525/EY/NEI NIH HHS/ -- PN2 EY016525-02S1/EY/NEI NIH HHS/ -- PN2 EY016525-03/EY/NEI NIH HHS/ -- PN2 EY016525-04/EY/NEI NIH HHS/ -- PN2 EY016525-05/EY/NEI NIH HHS/ -- R01 GM063817/GM/NIGMS NIH HHS/ -- R01 GM079429/GM/NIGMS NIH HHS/ -- R01 GM079429-03/GM/NIGMS NIH HHS/ -- R01 GM080139/GM/NIGMS NIH HHS/ -- R01 GM080139-03/GM/NIGMS NIH HHS/ -- R01 GM080139-04/GM/NIGMS NIH HHS/ -- R90 DK071504/DK/NIDDK NIH HHS/ -- R90 DK071504-03/DK/NIDDK NIH HHS/ -- T32 GM007276-30/GM/NIGMS NIH HHS/ -- T32 GM007276-31/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jan 21;463(7279):379-83. doi: 10.1038/nature08701.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20090755" target="_blank"〉PubMed〈/a〉

Description: The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. X-ray crystallography confirms that the structure matches the design for the most active of the enzymes, and binding site substitutions reprogram the substrate specificity. Designed stereoselective catalysts for carbon-carbon bond-forming reactions should be broadly useful in synthetic chemistry.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3241958/" 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/PMC3241958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siegel, Justin B -- Zanghellini, Alexandre -- Lovick, Helena M -- Kiss, Gert -- Lambert, Abigail R -- St Clair, Jennifer L -- Gallaher, Jasmine L -- Hilvert, Donald -- Gelb, Michael H -- Stoddard, Barry L -- Houk, Kendall N -- Michael, Forrest E -- Baker, David -- R01 GM075962/GM/NIGMS NIH HHS/ -- T32 GM008268/GM/NIGMS NIH HHS/ -- T32 GM008268-24/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2010 Jul 16;329(5989):309-13. doi: 10.1126/science.1190239.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20647463" target="_blank"〉PubMed〈/a〉

Description: Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified 〉300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235490/" 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/PMC3235490/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉International HIV Controllers Study -- Pereyra, Florencia -- Jia, Xiaoming -- McLaren, Paul J -- Telenti, Amalio -- de Bakker, Paul I W -- Walker, Bruce D -- Ripke, Stephan -- Brumme, Chanson J -- Pulit, Sara L -- Carrington, Mary -- Kadie, Carl M -- Carlson, Jonathan M -- Heckerman, David -- Graham, Robert R -- Plenge, Robert M -- Deeks, Steven G -- Gianniny, Lauren -- Crawford, Gabriel -- Sullivan, Jordan -- Gonzalez, Elena -- Davies, Leela -- Camargo, Amy -- Moore, Jamie M -- Beattie, Nicole -- Gupta, Supriya -- Crenshaw, Andrew -- Burtt, Noel P -- Guiducci, Candace -- Gupta, Namrata -- Gao, Xiaojiang -- Qi, Ying -- Yuki, Yuko -- Piechocka-Trocha, Alicja -- Cutrell, Emily -- Rosenberg, Rachel -- Moss, Kristin L -- Lemay, Paul -- O'Leary, Jessica -- Schaefer, Todd -- Verma, Pranshu -- Toth, Ildiko -- Block, Brian -- Baker, Brett -- Rothchild, Alissa -- Lian, Jeffrey -- Proudfoot, Jacqueline -- Alvino, Donna Marie L -- Vine, Seanna -- Addo, Marylyn M -- Allen, Todd M -- Altfeld, Marcus -- Henn, Matthew R -- Le Gall, Sylvie -- Streeck, Hendrik -- Haas, David W -- Kuritzkes, Daniel R -- Robbins, Gregory K -- Shafer, Robert W -- Gulick, Roy M -- Shikuma, Cecilia M -- Haubrich, Richard -- Riddler, Sharon -- Sax, Paul E -- Daar, Eric S -- Ribaudo, Heather J -- Agan, Brian -- Agarwal, Shanu -- Ahern, Richard L -- Allen, Brady L -- Altidor, Sherly -- Altschuler, Eric L -- Ambardar, Sujata -- Anastos, Kathryn -- Anderson, Ben -- Anderson, Val -- Andrady, Ushan -- Antoniskis, Diana -- Bangsberg, David -- Barbaro, Daniel -- Barrie, William -- Bartczak, J -- Barton, Simon -- Basden, Patricia -- Basgoz, Nesli -- Bazner, Suzane -- Bellos, Nicholaos C -- Benson, Anne M -- Berger, Judith -- Bernard, Nicole F -- Bernard, Annette M -- Birch, Christopher -- Bodner, Stanley J -- Bolan, Robert K -- Boudreaux, Emilie T -- Bradley, Meg -- Braun, James F -- Brndjar, Jon E -- Brown, Stephen J -- Brown, Katherine -- Brown, Sheldon T -- Burack, Jedidiah -- Bush, Larry M -- Cafaro, Virginia -- Campbell, Omobolaji -- Campbell, John -- Carlson, Robert H -- Carmichael, J Kevin -- Casey, Kathleen K -- Cavacuiti, Chris -- Celestin, Gregory -- Chambers, Steven T -- Chez, Nancy -- Chirch, Lisa M -- Cimoch, Paul J -- Cohen, Daniel -- Cohn, Lillian E -- Conway, Brian -- Cooper, David A -- Cornelson, Brian -- Cox, David T -- Cristofano, Michael V -- Cuchural, George Jr -- Czartoski, Julie L -- Dahman, Joseph M -- Daly, Jennifer S -- Davis, Benjamin T -- Davis, Kristine -- Davod, Sheila M -- DeJesus, Edwin -- Dietz, Craig A -- Dunham, Eleanor -- Dunn, Michael E -- Ellerin, Todd B -- Eron, Joseph J -- Fangman, John J W -- Farel, Claire E -- Ferlazzo, Helen -- Fidler, Sarah -- Fleenor-Ford, Anita -- Frankel, Renee -- Freedberg, Kenneth A -- French, Neel K -- Fuchs, Jonathan D -- Fuller, Jon D -- Gaberman, Jonna -- Gallant, Joel E -- Gandhi, Rajesh T -- Garcia, Efrain -- Garmon, Donald -- Gathe, Joseph C Jr -- Gaultier, Cyril R -- Gebre, Wondwoosen -- Gilman, Frank D -- Gilson, Ian -- Goepfert, Paul A -- Gottlieb, Michael S -- Goulston, Claudia -- Groger, Richard K -- Gurley, T Douglas -- Haber, Stuart -- Hardwicke, Robin -- Hardy, W David -- Harrigan, P Richard -- Hawkins, Trevor N -- Heath, Sonya -- Hecht, Frederick M -- Henry, W Keith -- Hladek, Melissa -- Hoffman, Robert P -- Horton, James M -- Hsu, Ricky K -- Huhn, Gregory D -- Hunt, Peter -- Hupert, Mark J -- Illeman, Mark L -- Jaeger, Hans -- Jellinger, Robert M -- John, Mina -- Johnson, Jennifer A -- Johnson, Kristin L -- Johnson, Heather -- Johnson, Kay -- Joly, Jennifer -- Jordan, Wilbert C -- Kauffman, Carol A -- Khanlou, Homayoon -- Killian, Robert K -- Kim, Arthur Y -- Kim, David D -- Kinder, Clifford A -- Kirchner, Jeffrey T -- Kogelman, Laura -- Kojic, Erna Milunka -- Korthuis, P Todd -- Kurisu, Wayne -- Kwon, Douglas S -- LaMar, Melissa -- Lampiris, Harry -- Lanzafame, Massimiliano -- Lederman, Michael M -- Lee, David M -- Lee, Jean M L -- Lee, Marah J -- Lee, Edward T Y -- Lemoine, Janice -- Levy, Jay A -- Llibre, Josep M -- Liguori, Michael A -- Little, Susan J -- Liu, Anne Y -- Lopez, Alvaro J -- Loutfy, Mono R -- Loy, Dawn -- Mohammed, Debbie Y -- Man, Alan -- Mansour, Michael K -- Marconi, Vincent C -- Markowitz, Martin -- Marques, Rui -- Martin, Jeffrey N -- Martin, Harold L Jr -- Mayer, Kenneth Hugh -- McElrath, M Juliana -- McGhee, Theresa A -- McGovern, Barbara H -- McGowan, Katherine -- McIntyre, Dawn -- Mcleod, Gavin X -- Menezes, Prema -- Mesa, Greg -- Metroka, Craig E -- Meyer-Olson, Dirk -- Miller, Andy O -- Montgomery, Kate -- Mounzer, Karam C -- Nagami, Ellen H -- Nagin, Iris -- Nahass, Ronald G -- Nelson, Margret O -- Nielsen, Craig -- Norene, David L -- O'Connor, David H -- Ojikutu, Bisola O -- Okulicz, Jason -- Oladehin, Olakunle O -- Oldfield, Edward C 3rd -- Olender, Susan A -- Ostrowski, Mario -- Owen, William F Jr -- Pae, Eunice -- Parsonnet, Jeffrey -- Pavlatos, Andrew M -- Perlmutter, Aaron M -- Pierce, Michael N -- Pincus, Jonathan M -- Pisani, Leandro -- Price, Lawrence Jay -- Proia, Laurie -- Prokesch, Richard C -- Pujet, Heather Calderon -- Ramgopal, Moti -- Rathod, Almas -- Rausch, Michael -- Ravishankar, J -- Rhame, Frank S -- Richards, Constance Shamuyarira -- Richman, Douglas D -- Rodes, Berta -- Rodriguez, Milagros -- Rose, Richard C 3rd -- Rosenberg, Eric S -- Rosenthal, Daniel -- Ross, Polly E -- Rubin, David S -- Rumbaugh, Elease -- Saenz, Luis -- Salvaggio, Michelle R -- Sanchez, William C -- Sanjana, Veeraf M -- Santiago, Steven -- Schmidt, Wolfgang -- Schuitemaker, Hanneke -- Sestak, Philip M -- Shalit, Peter -- Shay, William -- Shirvani, Vivian N -- Silebi, Vanessa I -- Sizemore, James M Jr -- Skolnik, Paul R -- Sokol-Anderson, Marcia -- Sosman, James M -- Stabile, Paul -- Stapleton, Jack T -- Starrett, Sheree -- Stein, Francine -- Stellbrink, Hans-Jurgen -- Sterman, F Lisa -- Stone, Valerie E -- Stone, David R -- Tambussi, Giuseppe -- Taplitz, Randy A -- Tedaldi, Ellen M -- Theisen, William -- Torres, Richard -- Tosiello, Lorraine -- Tremblay, Cecile -- Tribble, Marc A -- Trinh, Phuong D -- Tsao, Alice -- Ueda, Peggy -- Vaccaro, Anthony -- Valadas, Emilia -- Vanig, Thanes J -- Vecino, Isabel -- Vega, Vilma M -- Veikley, Wenoah -- Wade, Barbara H -- Walworth, Charles -- Wanidworanun, Chingchai -- Ward, Douglas J -- Warner, Daniel A -- Weber, Robert D -- Webster, Duncan -- Weis, Steve -- Wheeler, David A -- White, David J -- Wilkins, Ed -- Winston, Alan -- Wlodaver, Clifford G -- van't Wout, Angelique -- Wright, David P -- Yang, Otto O -- Yurdin, David L -- Zabukovic, Brandon W -- Zachary, Kimon C -- Zeeman, Beth -- Zhao, Meng -- AI030914/AI/NIAID NIH HHS/ -- AI068636/AI/NIAID NIH HHS/ -- AI069415/AI/NIAID NIH HHS/ -- AI069419/AI/NIAID NIH HHS/ -- AI069423/AI/NIAID NIH HHS/ -- AI069424/AI/NIAID NIH HHS/ -- AI069428/AI/NIAID NIH HHS/ -- AI069432/AI/NIAID NIH HHS/ -- AI069434/AI/NIAID NIH HHS/ -- AI069450/AI/NIAID NIH HHS/ -- AI069452/AI/NIAID NIH HHS/ -- AI069465/AI/NIAID NIH HHS/ -- AI069471/AI/NIAID NIH HHS/ -- AI069472/AI/NIAID NIH HHS/ -- AI069474/AI/NIAID NIH HHS/ -- AI069477/AI/NIAID NIH HHS/ -- AI069484/AI/NIAID NIH HHS/ -- AI069495/AI/NIAID NIH HHS/ -- AI069501/AI/NIAID NIH HHS/ -- AI069502/AI/NIAID NIH HHS/ -- AI069511/AI/NIAID NIH HHS/ -- AI069513/AI/NIAID NIH HHS/ -- AI069532/AI/NIAID NIH HHS/ -- AI069556/AI/NIAID NIH HHS/ -- AI077505/AI/NIAID NIH HHS/ -- AI087145/AI/NIAID NIH HHS/ -- AI25859/AI/NIAID NIH HHS/ -- AI27661/AI/NIAID NIH HHS/ -- AI28568/AI/NIAID NIH HHS/ -- AI30914/AI/NIAID NIH HHS/ -- AI34835/AI/NIAID NIH HHS/ -- AI34853/AI/NIAID NIH HHS/ -- AI38844/AI/NIAID NIH HHS/ -- AI46370/AI/NIAID NIH HHS/ -- AI68634/AI/NIAID NIH HHS/ -- AI69467/AI/NIAID NIH HHS/ -- AL32782/PHS HHS/ -- HHSN261200800001E/PHS HHS/ -- K23 DA019809/DA/NIDA NIH HHS/ -- K24 AI051966/AI/NIAID NIH HHS/ -- K24 AI064086/AI/NIAID NIH HHS/ -- K24 AI064086-05/AI/NIAID NIH HHS/ -- K24 AI069994/AI/NIAID NIH HHS/ -- K24 AI069994-04/AI/NIAID NIH HHS/ -- K24 AI069994-05/AI/NIAID NIH HHS/ -- K24AI069994/AI/NIAID NIH HHS/ -- KL2 RR024977/RR/NCRR NIH HHS/ -- MH071205/MH/NIMH NIH HHS/ -- MH085520/MH/NIMH NIH HHS/ -- P-30 AI27763/AI/NIAID NIH HHS/ -- P-30-AI060354/AI/NIAID NIH HHS/ -- P30 AI027763/AI/NIAID NIH HHS/ -- P30 AI027763-19/AI/NIAID NIH HHS/ -- P30 AI027763-20/AI/NIAID NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- P30 AI060354-08/AI/NIAID NIH HHS/ -- P30 AI060354-09/AI/NIAID NIH HHS/ -- R01 AI028568/AI/NIAID NIH HHS/ -- R01 AI028568-18/AI/NIAID NIH HHS/ -- R01 AI028568-19/AI/NIAID NIH HHS/ -- R01 AI028568-20/AI/NIAID NIH HHS/ -- R01 AI030914/AI/NIAID NIH HHS/ -- R01 AI030914-16/AI/NIAID NIH HHS/ -- R01 AI030914-17/AI/NIAID NIH HHS/ -- R01 AI077505/AI/NIAID NIH HHS/ -- R01 AI077505-04/AI/NIAID NIH HHS/ -- R01 AI077505-05/AI/NIAID NIH HHS/ -- R01 AI087145/AI/NIAID NIH HHS/ -- R01 AI087145-01/AI/NIAID NIH HHS/ -- R01 AI087145-02/AI/NIAID NIH HHS/ -- R01 MH054907/MH/NIMH NIH HHS/ -- R01 MH071205/MH/NIMH NIH HHS/ -- R01 MH071205-04/MH/NIMH NIH HHS/ -- R01 MH071205-05/MH/NIMH NIH HHS/ -- R24 AI067039/AI/NIAID NIH HHS/ -- R24 AI067039-06/AI/NIAID NIH HHS/ -- R24 AI067039-07/AI/NIAID NIH HHS/ -- R37 AI028568/AI/NIAID NIH HHS/ -- R37 AI028568-15/AI/NIAID NIH HHS/ -- RR024975/RR/NCRR NIH HHS/ -- T32 AI007061/AI/NIAID NIH HHS/ -- TL1 RR024978/RR/NCRR NIH HHS/ -- U01 AI027661-18/AI/NIAID NIH HHS/ -- U01 AI027661-19/AI/NIAID NIH HHS/ -- U01 AI032782-13/AI/NIAID NIH HHS/ -- U01 AI034835-07/AI/NIAID NIH HHS/ -- U01 AI034835-07S3/AI/NIAID NIH HHS/ -- U01 AI034853/AI/NIAID NIH HHS/ -- U01 AI034853-11/AI/NIAID NIH HHS/ -- U01 AI034853-12/AI/NIAID NIH HHS/ -- U01 AI038844-04/AI/NIAID NIH HHS/ -- U01 AI038844-04S1/AI/NIAID NIH HHS/ -- U01 AI038844-04S2/AI/NIAID NIH HHS/ -- U01 AI038844-04S3/AI/NIAID NIH HHS/ -- U01 AI046370-04/AI/NIAID NIH HHS/ -- U01 AI046370-05/AI/NIAID NIH HHS/ -- U01 AI069419/AI/NIAID NIH HHS/ -- U01 AI069419-05/AI/NIAID NIH HHS/ -- U01 AI069419-06/AI/NIAID NIH HHS/ -- U01 AI069423/AI/NIAID NIH HHS/ -- U01 AI069423-05/AI/NIAID NIH HHS/ -- U01 AI069423-06/AI/NIAID NIH HHS/ -- U01 AI069424/AI/NIAID NIH HHS/ -- U01 AI069424-05/AI/NIAID NIH HHS/ -- U01 AI069424-06/AI/NIAID NIH HHS/ -- U01 AI069428/AI/NIAID NIH HHS/ -- U01 AI069428-05/AI/NIAID NIH HHS/ -- U01 AI069428-06/AI/NIAID NIH HHS/ -- U01 AI069432/AI/NIAID NIH HHS/ -- U01 AI069432-05/AI/NIAID NIH HHS/ -- U01 AI069432-06/AI/NIAID NIH HHS/ -- U01 AI069434/AI/NIAID NIH HHS/ -- U01 AI069434-05/AI/NIAID NIH HHS/ -- U01 AI069434-06/AI/NIAID NIH HHS/ -- U01 AI069450/AI/NIAID NIH HHS/ -- U01 AI069450-05/AI/NIAID NIH HHS/ -- U01 AI069450-06/AI/NIAID NIH HHS/ -- U01 AI069452/AI/NIAID NIH HHS/ -- U01 AI069452-05/AI/NIAID NIH HHS/ -- U01 AI069452-06/AI/NIAID NIH HHS/ -- U01 AI069465/AI/NIAID NIH HHS/ -- U01 AI069465-05/AI/NIAID NIH HHS/ -- U01 AI069465-06/AI/NIAID NIH HHS/ -- U01 AI069467/AI/NIAID NIH HHS/ -- U01 AI069467-05/AI/NIAID NIH HHS/ -- U01 AI069467-06/AI/NIAID NIH HHS/ -- U01 AI069471/AI/NIAID NIH HHS/ -- U01 AI069471-05/AI/NIAID NIH HHS/ -- U01 AI069471-06/AI/NIAID NIH HHS/ -- U01 AI069472/AI/NIAID NIH HHS/ -- U01 AI069472-05/AI/NIAID NIH HHS/ -- U01 AI069472-06/AI/NIAID NIH HHS/ -- U01 AI069474/AI/NIAID NIH HHS/ -- U01 AI069474-05/AI/NIAID NIH HHS/ -- U01 AI069474-06/AI/NIAID NIH HHS/ -- U01 AI069477/AI/NIAID NIH HHS/ -- U01 AI069477-05/AI/NIAID NIH HHS/ -- U01 AI069477-06/AI/NIAID NIH HHS/ -- U01 AI069484/AI/NIAID NIH HHS/ -- U01 AI069484-05/AI/NIAID NIH HHS/ -- U01 AI069484-06/AI/NIAID NIH HHS/ -- U01 AI069495/AI/NIAID NIH HHS/ -- U01 AI069495-05/AI/NIAID NIH HHS/ -- U01 AI069495-06/AI/NIAID NIH HHS/ -- U01 AI069501/AI/NIAID NIH HHS/ -- U01 AI069501-05/AI/NIAID NIH HHS/ -- U01 AI069501-06/AI/NIAID NIH HHS/ -- U01 AI069502/AI/NIAID NIH HHS/ -- U01 AI069502-05/AI/NIAID NIH HHS/ -- U01 AI069502-06/AI/NIAID NIH HHS/ -- U01 AI069511/AI/NIAID NIH HHS/ -- U01 AI069511-05/AI/NIAID NIH HHS/ -- U01 AI069511-06/AI/NIAID NIH HHS/ -- U01 AI069513-05/AI/NIAID NIH HHS/ -- U01 AI069513-06/AI/NIAID NIH HHS/ -- U01 AI069532/AI/NIAID NIH HHS/ -- U01 AI069532-05/AI/NIAID NIH HHS/ -- U01 AI069532-06/AI/NIAID NIH HHS/ -- U01 AI069556-05/AI/NIAID NIH HHS/ -- U01 AI069556-06/AI/NIAID NIH HHS/ -- U01 MH085520/MH/NIMH NIH HHS/ -- U01 MH085520-01/MH/NIMH NIH HHS/ -- UL1 RR024131/RR/NCRR NIH HHS/ -- UL1 RR024131-06/RR/NCRR NIH HHS/ -- UL1 RR024131-07/RR/NCRR NIH HHS/ -- UL1 RR024975/RR/NCRR NIH HHS/ -- UL1 RR024975-04/RR/NCRR NIH HHS/ -- UL1 RR024975-05/RR/NCRR NIH HHS/ -- UM1 AI068634/AI/NIAID NIH HHS/ -- UM1 AI068634-06/AI/NIAID NIH HHS/ -- UM1 AI068634-07/AI/NIAID NIH HHS/ -- UM1 AI068636-06/AI/NIAID NIH HHS/ -- UM1 AI068636-07/AI/NIAID NIH HHS/ -- UM1 AI069477/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2010 Dec 10;330(6010):1551-7. doi: 10.1126/science.1195271. Epub 2010 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology (MIT) and Harvard, Boston, MA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21051598" target="_blank"〉PubMed〈/a〉

Description: Conventional protein structure determination from nuclear magnetic resonance data relies heavily on side-chain proton-to-proton distances. The necessary side-chain resonance assignment, however, is labor intensive and prone to error. Here we show that structures can be accurately determined without nuclear magnetic resonance (NMR) information on the side chains for proteins up to 25 kilodaltons by incorporating backbone chemical shifts, residual dipolar couplings, and amide proton distances into the Rosetta protein structure modeling methodology. These data, which are too sparse for conventional methods, serve only to guide conformational search toward the lowest-energy conformations in the folding landscape; the details of the computed models are determined by the physical chemistry implicit in the Rosetta all-atom energy function. The new method is not hindered by the deuteration required to suppress nuclear relaxation processes for proteins greater than 15 kilodaltons and should enable routine NMR structure determination for larger proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909653/" 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/PMC2909653/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raman, Srivatsan -- Lange, Oliver F -- Rossi, Paolo -- Tyka, Michael -- Wang, Xu -- Aramini, James -- Liu, Gaohua -- Ramelot, Theresa A -- Eletsky, Alexander -- Szyperski, Thomas -- Kennedy, Michael A -- Prestegard, James -- Montelione, Gaetano T -- Baker, David -- GM76222/GM/NIGMS NIH HHS/ -- P41 GM103390/GM/NIGMS NIH HHS/ -- R01 GM092802/GM/NIGMS NIH HHS/ -- R01 GM095693/GM/NIGMS NIH HHS/ -- RR005351/RR/NCRR NIH HHS/ -- U54 GM074958/GM/NIGMS NIH HHS/ -- U54 GM074958-05/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2010 Feb 19;327(5968):1014-8. doi: 10.1126/science.1183649. Epub 2010 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20133520" target="_blank"〉PubMed〈/a〉

Description: The manipulation of protein backbone structure to control interaction and function is a challenge for protein engineering. We integrated computational design with experimental selection for grafting the backbone and side chains of a two-segment HIV gp120 epitope, targeted by the cross-neutralizing antibody b12, onto an unrelated scaffold protein. The final scaffolds bound b12 with high specificity and with affinity similar to that of gp120, and crystallographic analysis of a scaffold bound to b12 revealed high structural mimicry of the gp120-b12 complex structure. The method can be generalized to design other functional proteins through backbone grafting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Azoitei, Mihai L -- Correia, Bruno E -- Ban, Yih-En Andrew -- Carrico, Chris -- Kalyuzhniy, Oleksandr -- Chen, Lei -- Schroeter, Alexandria -- Huang, Po-Ssu -- McLellan, Jason S -- Kwong, Peter D -- Baker, David -- Strong, Roland K -- Schief, William R -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Oct 21;334(6054):373-6. doi: 10.1126/science.1209368.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22021856" target="_blank"〉PubMed〈/a〉

Description: The structure of BPSL1549, a protein of unknown function from Burkholderia pseudomallei, reveals a similarity to Escherichia coli cytotoxic necrotizing factor 1. We found that BPSL1549 acted as a potent cytotoxin against eukaryotic cells and was lethal when administered to mice. Expression levels of bpsl1549 correlate with conditions expected to promote or suppress pathogenicity. BPSL1549 promotes deamidation of glutamine-339 of the translation initiation factor eIF4A, abolishing its helicase activity and inhibiting translation. We propose to name BPSL1549 Burkholderia lethal factor 1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364511/" 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/PMC3364511/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cruz-Migoni, Abimael -- Hautbergue, Guillaume M -- Artymiuk, Peter J -- Baker, Patrick J -- Bokori-Brown, Monika -- Chang, Chung-Te -- Dickman, Mark J -- Essex-Lopresti, Angela -- Harding, Sarah V -- Mahadi, Nor Muhammad -- Marshall, Laura E -- Mobbs, George W -- Mohamed, Rahmah -- Nathan, Sheila -- Ngugi, Sarah A -- Ong, Catherine -- Ooi, Wen Fong -- Partridge, Lynda J -- Phillips, Helen L -- Raih, M Firdaus -- Ruzheinikov, Sergei -- Sarkar-Tyson, Mitali -- Sedelnikova, Svetlana E -- Smither, Sophie J -- Tan, Patrick -- Titball, Richard W -- Wilson, Stuart A -- Rice, David W -- 085162/Wellcome Trust/United Kingdom -- BB/D011795/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/D524975/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/E025293/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- WT085162AIA/Wellcome Trust/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2011 Nov 11;334(6057):821-4. doi: 10.1126/science.1211915.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Biotechnology, Krebs Institute, University of Sheffield, Sheffield S10 2TN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22076380" target="_blank"〉PubMed〈/a〉

Description: Down's syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479956/" 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/PMC3479956/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reynolds, Louise E -- Watson, Alan R -- Baker, Marianne -- Jones, Tania A -- D'Amico, Gabriela -- Robinson, Stephen D -- Joffre, Carine -- Garrido-Urbani, Sarah -- Rodriguez-Manzaneque, Juan Carlos -- Martino-Echarri, Estefania -- Aurrand-Lions, Michel -- Sheer, Denise -- Dagna-Bricarelli, Franca -- Nizetic, Dean -- McCabe, Christopher J -- Turnell, Andrew S -- Kermorgant, Stephanie -- Imhof, Beat A -- Adams, Ralf -- Fisher, Elizabeth M C -- Tybulewicz, Victor L J -- Hart, Ian R -- Hodivala-Dilke, Kairbaan M -- 080174/Wellcome Trust/United Kingdom -- 12007/Cancer Research UK/United Kingdom -- A12007/Cancer Research UK/United Kingdom -- A3585/Cancer Research UK/United Kingdom -- G0501003/Medical Research Council/United Kingdom -- G0501003(75694)/Medical Research Council/United Kingdom -- G0601056/Medical Research Council/United Kingdom -- G0901609/Medical Research Council/United Kingdom -- MC_U117527252/Medical Research Council/United Kingdom -- U.1175.02.001.00001(60485)/Medical Research Council/United Kingdom -- England -- Nature. 2010 Jun 10;465(7299):813-7. doi: 10.1038/nature09106.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Adhesion and Angiogenesis Laboratory, Barts Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK. l.reynolds@qmul.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535211" target="_blank"〉PubMed〈/a〉

Description: Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323/" 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/PMC3468323/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baker, Darren J -- Wijshake, Tobias -- Tchkonia, Tamar -- LeBrasseur, Nathan K -- Childs, Bennett G -- van de Sluis, Bart -- Kirkland, James L -- van Deursen, Jan M -- AG13925/AG/NIA NIH HHS/ -- CA96985/CA/NCI NIH HHS/ -- P30 DK050456/DK/NIDDK NIH HHS/ -- R01 AG013925/AG/NIA NIH HHS/ -- R01 AG013925-14/AG/NIA NIH HHS/ -- R01 CA096985/CA/NCI NIH HHS/ -- R01 CA096985-10/CA/NCI NIH HHS/ -- England -- Nature. 2011 Nov 2;479(7372):232-6. doi: 10.1038/nature10600.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22048312" target="_blank"〉PubMed〈/a〉

Description: Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-beta-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073670/" 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/PMC4073670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sievers, Stuart A -- Karanicolas, John -- Chang, Howard W -- Zhao, Anni -- Jiang, Lin -- Zirafi, Onofrio -- Stevens, Jason T -- Munch, Jan -- Baker, David -- Eisenberg, David -- P50 AG016570/AG/NIA NIH HHS/ -- R01 AG029430/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 15;475(7354):96-100. doi: 10.1038/nature10154.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles, California 90095-1570, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21677644" target="_blank"〉PubMed〈/a〉