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  • 1
    Publication Date: 1996-08-16
    Description: Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Howard, A D -- Feighner, S D -- Cully, D F -- Arena, J P -- Liberator, P A -- Rosenblum, C I -- Hamelin, M -- Hreniuk, D L -- Palyha, O C -- Anderson, J -- Paress, P S -- Diaz, C -- Chou, M -- Liu, K K -- McKee, K K -- Pong, S S -- Chaung, L Y -- Elbrecht, A -- Dashkevicz, M -- Heavens, R -- Rigby, M -- Sirinathsinghji, D J -- Dean, D C -- Melillo, D G -- Patchett, A A -- Nargund, R -- Griffin, P R -- DeMartino, J A -- Gupta, S K -- Schaeffer, J M -- Smith, R G -- Van der Ploeg, L H -- New York, N.Y. -- Science. 1996 Aug 16;273(5277):974-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Merck Research Laboratories, Rahway, NJ 07065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8688086" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Base Sequence ; Cell Line ; Codon ; DNA, Complementary/genetics ; GTP-Binding Proteins/metabolism ; Growth Hormone/*secretion ; Hormones/*metabolism ; Humans ; Hypothalamus, Middle/chemistry ; Indoles/*metabolism/pharmacology ; Macaca mulatta ; Molecular Sequence Data ; Oligopeptides/*metabolism ; Pituitary Gland/chemistry ; RNA, Complementary/genetics ; Rats ; Receptors, Cell Surface/analysis/chemistry/genetics/*metabolism ; *Receptors, G-Protein-Coupled ; Receptors, Ghrelin ; Spiro Compounds/*metabolism/pharmacology ; Swine
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-11-26
    Description: Abscisic acid (ABA) is an essential hormone for plants to survive environmental stresses. At the center of the ABA signaling network is a subfamily of type 2C protein phosphatases (PP2Cs), which form exclusive interactions with ABA receptors and subfamily 2 Snfl-related kinase (SnRK2s). Here, we report a SnRK2-PP2C complex structure, which reveals marked similarity in PP2C recognition by SnRK2 and ABA receptors. In the complex, the kinase activation loop docks into the active site of PP2C, while the conserved ABA-sensing tryptophan of PP2C inserts into the kinase catalytic cleft, thus mimicking receptor-PP2C interactions. These structural results provide a simple mechanism that directly couples ABA binding to SnRK2 kinase activation and highlight a new paradigm of kinase-phosphatase regulation through mutual packing of their catalytic sites.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584687/" 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/PMC3584687/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soon, Fen-Fen -- Ng, Ley-Moy -- Zhou, X Edward -- West, Graham M -- Kovach, Amanda -- Tan, M H Eileen -- Suino-Powell, Kelly M -- He, Yuanzheng -- Xu, Yong -- Chalmers, Michael J -- Brunzelle, Joseph S -- Zhang, Huiming -- Yang, Huaiyu -- Jiang, Hualiang -- Li, Jun -- Yong, Eu-Leong -- Cutler, Sean -- Zhu, Jian-Kang -- Griffin, Patrick R -- Melcher, Karsten -- Xu, H Eric -- GM084041/GM/NIGMS NIH HHS/ -- R01 GM059138/GM/NIGMS NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2012 Jan 6;335(6064):85-8. doi: 10.1126/science.1215106. Epub 2011 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22116026" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/chemistry/*metabolism ; Amino Acid Sequence ; Arabidopsis/chemistry/*metabolism ; Arabidopsis Proteins/antagonists & inhibitors/*chemistry/*metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Enzyme Activation ; Models, Molecular ; *Molecular Mimicry ; Molecular Sequence Data ; Phosphoprotein Phosphatases/*chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/*chemistry/*metabolism ; Recombinant Fusion Proteins/chemistry/metabolism ; Signal Transduction
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2019
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 4
    Publication Date: 2015-08-11
    Description: The plant hormone jasmonate plays crucial roles in regulating plant responses to herbivorous insects and microbial pathogens and is an important regulator of plant growth and development. Key mediators of jasmonate signalling include MYC transcription factors, which are repressed by jasmonate ZIM-domain (JAZ) transcriptional repressors in the resting state. In the presence of active jasmonate, JAZ proteins function as jasmonate co-receptors by forming a hormone-dependent complex with COI1, the F-box subunit of an SCF-type ubiquitin E3 ligase. The hormone-dependent formation of the COI1-JAZ co-receptor complex leads to ubiquitination and proteasome-dependent degradation of JAZ repressors and release of MYC proteins from transcriptional repression. The mechanism by which JAZ proteins repress MYC transcription factors and how JAZ proteins switch between the repressor function in the absence of hormone and the co-receptor function in the presence of hormone remain enigmatic. Here we show that Arabidopsis MYC3 undergoes pronounced conformational changes when bound to the conserved Jas motif of the JAZ9 repressor. The Jas motif, previously shown to bind to hormone as a partly unwound helix, forms a complete alpha-helix that displaces the amino (N)-terminal helix of MYC3 and becomes an integral part of the MYC N-terminal fold. In this position, the Jas helix competitively inhibits MYC3 interaction with the MED25 subunit of the transcriptional Mediator complex. Our structural and functional studies elucidate a dynamic molecular switch mechanism that governs the repression and activation of a major plant hormone pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567411/" 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/PMC4567411/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Feng -- Yao, Jian -- Ke, Jiyuan -- Zhang, Li -- Lam, Vinh Q -- Xin, Xiu-Fang -- Zhou, X Edward -- Chen, Jian -- Brunzelle, Joseph -- Griffin, Patrick R -- Zhou, Mingguo -- Xu, H Eric -- Melcher, Karsten -- He, Sheng Yang -- R01 AI068718/AI/NIAID NIH HHS/ -- R01 GM102545/GM/NIGMS NIH HHS/ -- R01AI060761/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 10;525(7568):269-73. doi: 10.1038/nature14661. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. ; DOE Plant Research Laboratory, Michigan State University, East Lansing, Michigan 48824, USA. ; College of Plant Protection, Nanjing Agricultural University, No. 1 Weigang, 210095, Nanjing, Jiangsu Province, China. ; Department of Biological Sciences, Western Michigan University, Kalamazoo, Michigan 49008, USA. ; Department of Plant Biology, Michigan State University, East Lansing, Michigan 48824, USA. ; Department of Molecular Therapeutics, Translational Research Institute, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ; College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. ; Department of Molecular Pharmacology and Biological Chemistry, Life Sciences Collaborative Access Team, Synchrotron Research Center, Northwestern University, Argonne, Illinois 60439, USA. ; Key Laboratory of Receptor Research, VARI-SIMM Center, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. ; Howard Hughes Medical Institute, Michigan State University, East Lansing, Michigan 48824, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258305" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Apoproteins/chemistry/metabolism ; *Arabidopsis/chemistry/metabolism ; Arabidopsis Proteins/*antagonists & inhibitors/*chemistry/genetics/*metabolism ; Binding, Competitive/genetics ; Crystallography, X-Ray ; Cyclopentanes/*metabolism ; Models, Molecular ; Nuclear Proteins/metabolism ; Oxylipins/*metabolism ; Plant Growth Regulators/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding/genetics ; Protein Conformation ; Repressor Proteins/*chemistry/genetics/*metabolism ; *Signal Transduction ; Trans-Activators/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Ubiquitination
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2015-10-28
    Description: Selective neuronal loss is a hallmark of neurodegenerative diseases, which, counterintuitively, are often caused by mutations in widely expressed genes. Charcot-Marie-Tooth (CMT) diseases are the most common hereditary peripheral neuropathies, for which there are no effective therapies. A subtype of these diseases--CMT type 2D (CMT2D)--is caused by dominant mutations in GARS, encoding the ubiquitously expressed enzyme glycyl-transfer RNA (tRNA) synthetase (GlyRS). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons, leading to deficits in distal motor function. How mutations in GlyRS (GlyRS(CMT2D)) are linked to motor neuron vulnerability has remained elusive. Here we report that GlyRS(CMT2D) acquires a neomorphic binding activity that directly antagonizes an essential signalling pathway for motor neuron survival. We find that CMT2D mutations alter the conformation of GlyRS, enabling GlyRS(CMT2D) to bind the neuropilin 1 (Nrp1) receptor. This aberrant interaction competitively interferes with the binding of the cognate ligand vascular endothelial growth factor (VEGF) to Nrp1. Genetic reduction of Nrp1 in mice worsens CMT2D symptoms, whereas enhanced expression of VEGF improves motor function. These findings link the selective pathology of CMT2D to the neomorphic binding activity of GlyRS(CMT2D) that antagonizes the VEGF-Nrp1 interaction, and indicate that the VEGF-Nrp1 signalling axis is an actionable target for treating CMT2D.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754353/" 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/PMC4754353/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Weiwei -- Bai, Ge -- Zhou, Huihao -- Wei, Na -- White, Nicholas M -- Lauer, Janelle -- Liu, Huaqing -- Shi, Yi -- Dumitru, Calin Dan -- Lettieri, Karen -- Shubayev, Veronica -- Jordanova, Albena -- Guergueltcheva, Velina -- Griffin, Patrick R -- Burgess, Robert W -- Pfaff, Samuel L -- Yang, Xiang-Lei -- R01 GM088278/GM/NIGMS NIH HHS/ -- R01 NS037116/NS/NINDS NIH HHS/ -- R01 NS054154/NS/NINDS NIH HHS/ -- R01 NS054172/NS/NINDS NIH HHS/ -- R01GM088278/GM/NIGMS NIH HHS/ -- R01NS054154/NS/NINDS NIH HHS/ -- R21 NS084254/NS/NINDS NIH HHS/ -- R21NS084254/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Oct 29;526(7575):710-4. doi: 10.1038/nature15510. Epub 2015 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA. ; Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA. ; Department of Anesthesiology, University of California San Diego, La Jolla, California 92093, USA. ; Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, BE-2610 Antwerp, Belgium. ; Department of Neurology, Medical University of Sofia, 1431 Sofia, Bulgaria. ; The Jackson Laboratory, Bar Harbor, Maine 04609, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503042" target="_blank"〉PubMed〈/a〉
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  • 6
    Publication Date: 2011-05-27
    Description: Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatic triglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150801/" 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/PMC3150801/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jae Man -- Lee, Yoon Kwang -- Mamrosh, Jennifer L -- Busby, Scott A -- Griffin, Patrick R -- Pathak, Manish C -- Ortlund, Eric A -- Moore, David D -- DK-079638/DK/NIDDK NIH HHS/ -- R01 CA134873/CA/NCI NIH HHS/ -- R01 DK068804/DK/NIDDK NIH HHS/ -- R01 DK083572/DK/NIDDK NIH HHS/ -- R01 DK083572-02/DK/NIDDK NIH HHS/ -- T32 DK007696/DK/NIDDK NIH HHS/ -- U54 MH084512/MH/NIMH NIH HHS/ -- England -- Nature. 2011 May 25;474(7352):506-10. doi: 10.1038/nature10111.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Developmental Biology, 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/21614002" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bile Acids and Salts/biosynthesis/metabolism/pharmacology ; Blood Glucose/metabolism ; Cell Line ; Disease Models, Animal ; Fatty Liver/drug therapy/enzymology ; HeLa Cells ; Homeostasis/drug effects ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin Resistance/physiology ; Ligands ; Lipogenesis/drug effects ; Liver/drug effects/enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphatidylcholines/*metabolism/pharmacology ; Protein Binding ; Receptors, Cytoplasmic and Nuclear/agonists/deficiency/genetics/*metabolism ; Signal Transduction/drug effects ; Triglycerides/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
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  • 7
    Publication Date: 2015-07-23
    Description: G-protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signalling to numerous G-protein-independent pathways. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. Together with extensive biochemical and mutagenesis data, the structure reveals an overall architecture of the rhodopsin-arrestin assembly in which rhodopsin uses distinct structural elements, including transmembrane helix 7 and helix 8, to recruit arrestin. Correspondingly, arrestin adopts the pre-activated conformation, with a approximately 20 degrees rotation between the amino and carboxy domains, which opens up a cleft in arrestin to accommodate a short helix formed by the second intracellular loop of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signalling and demonstrates the power of X-ray lasers for advancing the frontiers of structural biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521999/" 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/PMC4521999/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Yanyong -- Zhou, X Edward -- Gao, Xiang -- He, Yuanzheng -- Liu, Wei -- Ishchenko, Andrii -- Barty, Anton -- White, Thomas A -- Yefanov, Oleksandr -- Han, Gye Won -- Xu, Qingping -- de Waal, Parker W -- Ke, Jiyuan -- Tan, M H Eileen -- Zhang, Chenghai -- Moeller, Arne -- West, Graham M -- Pascal, Bruce D -- Van Eps, Ned -- Caro, Lydia N -- Vishnivetskiy, Sergey A -- Lee, Regina J -- Suino-Powell, Kelly M -- Gu, Xin -- Pal, Kuntal -- Ma, Jinming -- Zhi, Xiaoyong -- Boutet, Sebastien -- Williams, Garth J -- Messerschmidt, Marc -- Gati, Cornelius -- Zatsepin, Nadia A -- Wang, Dingjie -- James, Daniel -- Basu, Shibom -- Roy-Chowdhury, Shatabdi -- Conrad, Chelsie E -- Coe, Jesse -- Liu, Haiguang -- Lisova, Stella -- Kupitz, Christopher -- Grotjohann, Ingo -- Fromme, Raimund -- Jiang, Yi -- Tan, Minjia -- Yang, Huaiyu -- Li, Jun -- Wang, Meitian -- Zheng, Zhong -- Li, Dianfan -- Howe, Nicole -- Zhao, Yingming -- Standfuss, Jorg -- Diederichs, Kay -- Dong, Yuhui -- Potter, Clinton S -- Carragher, Bridget -- Caffrey, Martin -- Jiang, Hualiang -- Chapman, Henry N -- Spence, John C H -- Fromme, Petra -- Weierstall, Uwe -- Ernst, Oliver P -- Katritch, Vsevolod -- Gurevich, Vsevolod V -- Griffin, Patrick R -- Hubbell, Wayne L -- Stevens, Raymond C -- Cherezov, Vadim -- Melcher, Karsten -- Xu, H Eric -- DK071662/DK/NIDDK NIH HHS/ -- EY005216/EY/NEI NIH HHS/ -- EY011500/EY/NEI NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM077561/GM/NIGMS NIH HHS/ -- GM095583/GM/NIGMS NIH HHS/ -- GM097463/GM/NIGMS NIH HHS/ -- GM102545/GM/NIGMS NIH HHS/ -- GM103310/GM/NIGMS NIH HHS/ -- GM104212/GM/NIGMS NIH HHS/ -- GM108635/GM/NIGMS NIH HHS/ -- P30EY000331/EY/NEI NIH HHS/ -- P41 GM103310/GM/NIGMS NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- P41RR001209/RR/NCRR NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- R01 DK066202/DK/NIDDK NIH HHS/ -- R01 DK071662/DK/NIDDK NIH HHS/ -- R01 EY011500/EY/NEI NIH HHS/ -- R01 GM087413/GM/NIGMS NIH HHS/ -- R01 GM109955/GM/NIGMS NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U54 GM094586/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):561-7. doi: 10.1038/nature14656. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. ; Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA. ; Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA. ; Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany. ; Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA. ; 1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ; The National Resource for Automated Molecular Microscopy, New York Structural Biology Center, New York, New York 10027, USA. ; Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ; Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA. ; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA. ; Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA. ; 1] Linac Coherent Light Source (LCLS), SLAC National Accelerator Laboratory, Menlo Park, California 94025, USA [2] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, Arizona State University, Tempe, Arizona 85287, USA. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Beijing Computational Science Research Center, Haidian District, Beijing 10084, China. ; 1] Department of Chemistry and Biochemistry, and Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287-1604, USA [2] Department of Physics, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA. ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. ; Department of Obstetrics &Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. ; Swiss Light Source at Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA. ; School of Medicine and School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland. ; 1] BioXFEL, NSF Science and Technology Center, 700 Ellicott Street, Buffalo, New York 14203, USA [2] Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA. ; Laboratory of Biomolecular Research at Paul Scherrer Institute, CH-5232 Villigen, Switzerland. ; Department of Biology, Universitat Konstanz, 78457 Konstanz, Germany. ; Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China. ; 1] Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany [2] Centre for Ultrafast Imaging, 22761 Hamburg, Germany. ; 1] Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; 1] Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [2] Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China. ; 1] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA [2] VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200343" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arrestin/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Disulfides/chemistry/metabolism ; Humans ; Lasers ; Mice ; Models, Molecular ; Multiprotein Complexes/biosynthesis/chemistry/metabolism ; Protein Binding ; Reproducibility of Results ; Rhodopsin/*chemistry/*metabolism ; Signal Transduction ; X-Rays
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  • 8
    Publication Date: 2016-01-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Weiwei -- Bai, Ge -- Zhou, Huihao -- Wei, Na -- White, Nicholas M -- Lauer, Janelle -- Liu, Huaqing -- Shi, Yi -- Dan Dumitru, Calin -- Lettieri, Karen -- Shubayev, Veronica -- Jordanova, Albena -- Guergueltcheva, Velina -- Griffin, Patrick R -- Burgess, Robert W -- Pfaff, Samuel L -- Yang, Xiang-Lei -- England -- Nature. 2016 Apr 21;532(7599):402. doi: 10.1038/nature16499. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789244" target="_blank"〉PubMed〈/a〉
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2011-09-06
    Description: PPARgamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARgamma, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARgamma drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARgamma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" 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/PMC3179551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Jang Hyun -- Banks, Alexander S -- Kamenecka, Theodore M -- Busby, Scott A -- Chalmers, Michael J -- Kumar, Naresh -- Kuruvilla, Dana S -- Shin, Youseung -- He, Yuanjun -- Bruning, John B -- Marciano, David P -- Cameron, Michael D -- Laznik, Dina -- Jurczak, Michael J -- Schurer, Stephan C -- Vidovic, Dusica -- Shulman, Gerald I -- Spiegelman, Bruce M -- Griffin, Patrick R -- 1RC4DK090861/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 GM084041-03/GM/NIGMS NIH HHS/ -- R01-GM084041/GM/NIGMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-30/DK/NIDDK NIH HHS/ -- R37 DK031405-31/DK/NIDDK NIH HHS/ -- RC4 DK090861/DK/NIDDK NIH HHS/ -- RC4 DK090861-01/DK/NIDDK NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- U54 MH074404/MH/NIMH NIH HHS/ -- U54 MH074404-01/MH/NIMH NIH HHS/ -- U54-MH074404/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Sep 4;477(7365):477-81. doi: 10.1038/nature10383.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21892191" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/drug effects/metabolism ; Adipose Tissue, White/drug effects/metabolism ; Animals ; Biphenyl Compounds/chemistry/pharmacology ; Body Fluids/drug effects ; COS Cells ; Cercopithecus aethiops ; Cyclin-Dependent Kinase 5/*antagonists & inhibitors ; Dietary Fats/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Hypoglycemic Agents/adverse effects/chemistry/*pharmacology ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Models, Molecular ; Obesity/chemically induced/metabolism ; Osteogenesis/drug effects ; PPAR gamma/agonists/chemistry/*metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Thiazolidinediones/adverse effects/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; Weight Gain/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2011-04-19
    Description: T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors alpha and gammat (RORalpha and RORgammat, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORalpha and RORgammat and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORalpha and RORgammat, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORalpha and RORgammat to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148894/" 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/PMC3148894/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solt, Laura A -- Kumar, Naresh -- Nuhant, Philippe -- Wang, Yongjun -- Lauer, Janelle L -- Liu, Jin -- Istrate, Monica A -- Kamenecka, Theodore M -- Roush, William R -- Vidovic, Dusica -- Schurer, Stephan C -- Xu, Jihong -- Wagoner, Gail -- Drew, Paul D -- Griffin, Patrick R -- Burris, Thomas P -- DK080201/DK/NIDDK NIH HHS/ -- DK088499/DK/NIDDK NIH HHS/ -- DK089984/DK/NIDDK NIH HHS/ -- GM084041/GM/NIGMS NIH HHS/ -- MH084512/MH/NIMH NIH HHS/ -- R01 DK080201/DK/NIDDK NIH HHS/ -- R01 DK080201-06/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 MH092769/MH/NIMH NIH HHS/ -- U54 MH084512/MH/NIMH NIH HHS/ -- U54 MH084512-02/MH/NIMH NIH HHS/ -- U54MH074404/MH/NIMH NIH HHS/ -- England -- Nature. 2011 Apr 28;472(7344):491-4. doi: 10.1038/nature10075. Epub 2011 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21499262" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/*drug effects/immunology ; Cell Differentiation/*drug effects ; Drug Inverse Agonism ; HEK293 Cells ; Humans ; Interleukin-17/biosynthesis/immunology ; Interleukins/biosynthesis/immunology ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Nuclear Receptor Subfamily 1, Group F, Member 1/antagonists & ; inhibitors/genetics/metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & ; inhibitors/genetics/metabolism ; Sulfonamides/*pharmacology ; Th17 Cells/*cytology/drug effects/*immunology/secretion ; Thiazoles/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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