Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.
David M. Thal,Bingfa Sun,Dan Feng,Vindhya Nawaratne,Katie Leach,Christian C. Felder,Mark G. Bures,David A. Evans,William I. Weis,Priti Bachhawat,Tong Sun Kobilka,Patrick M. Sexton,Brian K. Kobilka,Arthur Christopoulos +13 more
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TLDR
Comparison of crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family.Abstract:
Muscarinic M1–M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer’s disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains. X-ray crystal structures of the M1 and M4 muscarinic acetylcholine receptors, revealing differences in the orthosteric and allosteric binding sites that help to explain the subtype selectivity of drugs targeting this family of receptors. Arthur Christopoulos and colleagues present the first X-ray crystal structures of the M1 and M4 muscarinic acetylcholine receptors, G-protein-coupled receptors (GPCRs) that regulate many vital functions of the central and peripheral nervous systems. The structures reveal differences in the orthosteric and allosteric binding sites that help to explain the subtype selectivity of drugs targeting this family of receptors. The M1 and M4 receptor subtypes are potential drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia.read more
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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals
James J. Lee,Robbee Wedow,Aysu Okbay,Edward Kong,Omeed Maghzian,Meghan Zacher,Tuan Anh Nguyen-Viet,Peter Bowers,Julia Sidorenko,Julia Sidorenko,Richard Karlsson Linnér,Richard Karlsson Linnér,Mark Alan Fontana,Mark Alan Fontana,Tushar Kundu,Chanwook Lee,Hui Li,Ruoxi Li,Rebecca Royer,Pascal Timshel,Pascal Timshel,Raymond K. Walters,Raymond K. Walters,Emily A. Willoughby,Loic Yengo,Maris Alver,Yanchun Bao,David W. Clark,Felix R. Day,Nicholas A. Furlotte,Peter K. Joshi,Peter K. Joshi,Kathryn E. Kemper,Aaron Kleinman,Claudia Langenberg,Reedik Mägi,Joey W. Trampush,Shefali S. Verma,Yang Wu,Max Lam,Jing Hua Zhao,Zhili Zheng,Zhili Zheng,Jason D. Boardman,Harry Campbell,Jeremy Freese,Kathleen Mullan Harris,Caroline Hayward,Pamela Herd,Pamela Herd,Meena Kumari,Todd Lencz,Todd Lencz,Jian'an Luan,Anil K. Malhotra,Anil K. Malhotra,Andres Metspalu,Lili Milani,Ken K. Ong,John R. B. Perry,David J. Porteous,Marylyn D. Ritchie,Melissa C. Smart,Blair H. Smith,Joyce Y. Tung,Nicholas J. Wareham,James F. Wilson,Jonathan P. Beauchamp,Dalton Conley,Tõnu Esko,Steven F. Lehrer,Steven F. Lehrer,Steven F. Lehrer,Patrik K. E. Magnusson,Sven Oskarsson,Tune H. Pers,Tune H. Pers,Matthew R. Robinson,Matthew R. Robinson,Kevin Thom,Chelsea Watson,Christopher F. Chabris,Michelle N. Meyer,David Laibson,Jian Yang,Magnus Johannesson,Philipp Koellinger,Philipp Koellinger,Patrick Turley,Patrick Turley,Peter M. Visscher,Daniel J. Benjamin,Daniel J. Benjamin,David Cesarini,David Cesarini +94 more
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
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GPCR Dynamics: Structures in Motion
TL;DR: What is currently known about the flexibility and dynamics of GPCRs, as determined through crystallography, spectroscopy, and computer simulations is reviewed.
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Crystal Structure of the Human Cannabinoid Receptor CB2.
Tian Hua,Kiran Vemuri,Mengchen Pu,Lu Qu,Lu Qu,Gye Won Han,Yiran Wu,Suwen Zhao,Wenqing Shui,Shanshan Li,Anisha Korde,Robert B. Laprairie,Edward L. Stahl,Jo-Hao Ho,Nikolai Zvonok,Han Zhou,Irina Kufareva,Beili Wu,Qiang Zhao,Michael A. Hanson,Laura M. Bohn,Alexandros Makriyannis,Raymond C. Stevens,Raymond C. Stevens,Zhi-Jie Liu,Zhi-Jie Liu +25 more
TL;DR: The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding and provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids.
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Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype Selectivity
Alisa Glukhova,David M. Thal,Anh Nguyen,Elizabeth A. Vecchio,Manuela Jörg,Peter J. Scammells,Lauren T. May,Patrick M. Sexton,Arthur Christopoulos +8 more
TL;DR: These findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain.
Journal ArticleDOI
Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes.
TL;DR: Cryo–electron microscopy structures of M1R in complex with G11 and M2R incomplex with GoA are presented and compared to provide a framework for understanding the molecular determinants of G-protein coupling selectivity.
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