Activation mechanism of the β2-adrenergic receptor
Ron O. Dror,Daniel H. Arlow,Paul Maragakis,Thomas J. Mildorf,Albert C. Pan,Huafeng Xu,David W. Borhani,David E. Shaw +7 more
TLDR
An activation mechanism for the β2-adrenergic receptor, a prototypical GPCR, is proposed based on atomic-level simulations in which an agonist-bound receptor transitions spontaneously from the active to the inactive crystallographically observed conformation.Abstract:
A third of marketed drugs act by binding to a G-protein-coupled receptor (GPCR) and either triggering or preventing receptor activation. Although recent crystal structures have provided snapshots of both active and inactive functional states of GPCRs, these structures do not reveal the mechanism by which GPCRs transition between these states. Here we propose an activation mechanism for the β2-adrenergic receptor, a prototypical GPCR, based on atomic-level simulations in which an agonist-bound receptor transitions spontaneously from the active to the inactive crystallographically observed conformation. A loosely coupled allosteric network, comprising three regions that can each switch individually between multiple distinct conformations, links small perturbations at the extracellular drug-binding site to large conformational changes at the intracellular G-protein-binding site. Our simulations also exhibit an intermediate that may represent a receptor conformation to which a G protein binds during activation, and suggest that the first structural changes during receptor activation often take place on the intracellular side of the receptor, far from the drug-binding site. By capturing this fundamental signaling process in atomic detail, our results may provide a foundation for the design of drugs that control receptor signaling more precisely by stabilizing specific receptor conformations.read more
Citations
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Journal ArticleDOI
Molecular signatures of G-protein-coupled receptors.
AJ Venkatakrishnan,Xavier Deupi,Guillaume Lebon,Christopher G. Tate,Gebhard F. X. Schertler,Gebhard F. X. Schertler,M. Madan Babu +6 more
TL;DR: Through a systematic analysis of high-resolution GPCR structures, a conserved network of non-covalent contacts that defines the G PCR fold is uncovered and characteristic features of ligand binding and conformational changes during receptor activation are revealed.
Journal ArticleDOI
Biomolecular Simulation: A Computational Microscope for Molecular Biology
TL;DR: The rapidly evolving state of the art for atomic-level biomolecular simulation is described, the types of biological discoveries that can now be made through simulation are illustrated, and challenges motivating continued innovation in this field are discussed.
Journal ArticleDOI
Molecular Dynamics Simulation for All.
TL;DR: The types of information molecular dynamics simulations can provide and the ways in which they typically motivate further experimental work are described.
Journal ArticleDOI
The Dynamic Process of β2-Adrenergic Receptor Activation
Rie Nygaard,Yaozhong Zou,Ron O. Dror,Thomas J. Mildorf,Daniel H. Arlow,Aashish Manglik,Albert C. Pan,Corey W. Liu,Juan Jose Fung,Michael P. Bokoch,Foon Sun Thian,Tong Sun Kobilka,David E. Shaw,Luciano Mueller,R. Scott Prosser,Brian K. Kobilka +15 more
TL;DR: NMR spectroscopy is used to characterize the conformational dynamics of the transmembrane core of the β(2)-adrenergic receptor (β(2)AR), a prototypical GPCR, and shows that for β( 2)AR, unlike rhodopsin, an agonist alone does not stabilize a fully active conformation.
Journal ArticleDOI
The Molecular Basis of G Protein-Coupled Receptor Activation.
William I. Weis,Brian K. Kobilka +1 more
TL;DR: Molecular understanding of the allosteric coupling between ligand binding and G protein or arrestin interaction is emerging from structures of several GPCRs crystallized in inactive and active states, spectroscopic data, and computer simulations.
References
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Alexander D. MacKerell,D. Bashford,M. Bellott,Roland L. Dunbrack,Jeffrey D. Evanseck,Martin J. Field,Stefan Fischer,Jiali Gao,H. Guo,S. Ha,Diane Joseph-McCarthy,L. Kuchnir,K. Kuczera,F. T. K. Lau,C. Mattos,Stephen W. Michnick,Thien H. Ngo,D. T. Nguyen,B. Prodhom,W. E. Reiher,Benoît Roux,M. Schlenkrich,Jeremy C. Smith,Roland H. Stote,John E. Straub,Masakatsu Watanabe,J. Wiórkiewicz-Kuczera,D. Yin,Martin Karplus +28 more
TL;DR: The results demonstrate that use of ab initio structural and energetic data by themselves are not sufficient to obtain an adequate backbone representation for peptides and proteins in solution and in crystals.
Journal ArticleDOI
Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor
Krzysztof Palczewski,Takashi Kumasaka,Tetsuya Hori,Craig A. Behnke,H. Motoshima,Brian A. Fox,I. Le Trong,David C. Teller,Tetsuji Okada,Ronald E. Stenkamp,Masaki Yamamoto,Masashi Miyano +11 more
TL;DR: This article determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution and found that the highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the sevenhelix transmembrane motif.
Journal ArticleDOI
High-Resolution Crystal Structure of an Engineered Human β2-Adrenergic G Protein–Coupled Receptor
Vadim Cherezov,Daniel M. Rosenbaum,Michael A. Hanson,Søren G. F. Rasmussen,Foon Sun Thian,Tong Sun Kobilka,Hee Jung Choi,Peter Kuhn,William I. Weis,Brian K. Kobilka,Raymond C. Stevens +10 more
TL;DR: Although the location of carazolol in the β2-adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand-binding site and other regions highlight the challenges in using rhodopin as a template model for this large receptor family.
Journal ArticleDOI
Crystal structure of the β2 adrenergic receptor-Gs protein complex.
Søren G. F. Rasmussen,Brian T. DeVree,Yaozhong Zou,Andrew C. Kruse,Ka Young Chung,Tong Sun Kobilka,Foon Sun Thian,Pil Seok Chae,Els Pardon,Els Pardon,Diane M. Calinski,Jesper Mosolff Mathiesen,Syed T. A. Shah,Joseph A. Lyons,Martin Caffrey,Samuel H. Gellman,Jan Steyaert,Jan Steyaert,Georgios Skiniotis,William I. Weis,Roger K. Sunahara,Brian K. Kobilka +21 more
TL;DR: This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR and the most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain.
Book ChapterDOI
[19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors
TL;DR: This chapter discusses the integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors (GPCR) and expects increased rate of success achieved by molecular modeling and computational simulation methods in providing structural insights relevant to the functions of biological molecules.
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