Ligand modulation of sidechain dynamics in a wild-type human GPCR

Clark, Lindsay D.; Dikiy, Igor; Chapman, Karen; Rödström, Karin E. J.; Aramini, James; LeVine, Michael V.; Khelashvili, George; Rasmussen, Søren G. F.; Gardner, Kevin H.; Rosenbaum, Daniel M.

doi:10.7554/elife.28505

Ligand modulation of sidechain dynamics in a wild-type human GPCR

Journal Article · Fri Oct 06 00:00:00 EDT 2017 · eLife

DOI:https://doi.org/10.7554/elife.28505· OSTI ID:1628874

^[1]; ^[2]; Chapman, Karen ^[3]; Rödström, Karin E. J. ^[4]; Aramini, James ^[2]; LeVine, Michael V. ^[5]; ^[5]; Rasmussen, Søren G. F. ^[4]; ^[2]; ^[6]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Biophysics and Molecular Biophysics Graduate Program; DOE/OSTI
City Univ. of New York (CUNY), NY (United States)
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Biophysics
Univ. of Copenhagen (Denmark). Dept. of Neuroscience and Pharmacology
Cornell Univ., Ithaca, NY (United States). Weill Medical College, Dept. of Physiology and Biophysics and Inst. for Computational Bioscience
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Biophysics and Molecular Biophysics Graduate Program

GPCRs regulate all aspects of human physiology, and biophysical studies have deepened our understanding of GPCR conformational regulation by different ligands. Yet there is no experimental evidence for how sidechain dynamics control allosteric transitions between GPCR conformations. To address this deficit, we generated samples of a wild-type GPCR (A_2AR) that are deuterated apart from ¹H/¹³C NMR probes at isoleucine δ1 methyl groups, which facilitated ¹H/¹³C methyl TROSY NMR measurements with opposing ligands. Our data indicate that low [Na⁺] is required to allow large agonist-induced structural changes in A_2AR, and that patterns of sidechain dynamics substantially differ between agonist (NECA) and inverse agonist (ZM241385) bound receptors, with the inverse agonist suppressing fast ps-ns timescale motions at the G protein binding site. Our approach to GPCR NMR creates a framework for exploring how different regions of a receptor respond to different ligands or signaling proteins through modulation of fast ps-ns sidechain dynamics.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: American Heart Association (AHA); Danish Council for Independent Research (DFF); Lundbeck Foundation; National Institutes of Health (NIH); National Science Foundation (NSF); Packard Foundation; USDOE Office of Science (SC); Welch Foundation

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1628874

Journal Information:: eLife, Journal Name: eLife Vol. 6; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches Jones, Andrew J. Y.; Gabriel, Florian; Tandale, Aditi Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.58724	text	January 2020
Spotlight on the Ballet of Proteins: The Structural Dynamic Properties of Proteins Illuminated by Solution NMR Tokunaga, Yuji; Viennet, Thibault; Arthanari, Haribabu International Journal of Molecular Sciences, Vol. 21, Issue 5 https://doi.org/10.3390/ijms21051829	journal	March 2020
Deuteration and selective labeling of alanine methyl groups of β2-adrenergic receptor expressed in a baculovirus-insect cell expression system Kofuku, Yutaka; Yokomizo, Tomoki; Imai, Shunsuke Journal of Biomolecular NMR, Vol. 71, Issue 3 https://doi.org/10.1007/s10858-018-0174-5	journal	March 2018
On the use of Pichia pastoris for isotopic labeling of human GPCRs for NMR studies Clark, Lindsay; Dikiy, Igor; Rosenbaum, Daniel M. Journal of Biomolecular NMR, Vol. 71, Issue 4 https://doi.org/10.1007/s10858-018-0204-3	journal	August 2018
Improved strategy for isoleucine 1H/13C methyl labeling in Pichia pastoris Ali, Rustam; Clark, Lindsay D.; Zahm, Jacob A. Journal of Biomolecular NMR, Vol. 73, Issue 12 https://doi.org/10.1007/s10858-019-00281-1	journal	September 2019
GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures Shimada, Ichio; Ueda, Takumi; Kofuku, Yutaka Nature Reviews Drug Discovery, Vol. 18, Issue 1 https://doi.org/10.1038/nrd.2018.180	journal	November 2018
A _2A adenosine receptor functional states characterized by ¹⁹ F-NMR Sušac, Lukas; Eddy, Matthew T.; Didenko, Tatiana Proceedings of the National Academy of Sciences, Vol. 115, Issue 50 https://doi.org/10.1073/pnas.1813649115	journal	November 2018
Solution NMR: A powerful tool for structural and functional studies of membrane proteins in reconstituted environments Puthenveetil, Robbins; Vinogradova, Olga Journal of Biological Chemistry, Vol. 294, Issue 44 https://doi.org/10.1074/jbc.rev119.009178	journal	September 2019

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