Allosteric Coupling of Drug Binding and Intracellular Signaling in the A2A Adenosine Receptor

Matthew T Eddy; Ming-Yue Lee; Zhan-Guo Gao; Kate L White; Tatiana Didenko; Reto Horst; Martin Audet; Pawel Stanczak; Kyle M McClary; Gye Won Han; Kenneth A Jacobson; Raymond C Stevens; Kurt Wüthrich

doi:10.1016/j.cell.2017.12.004

Allosteric Coupling of Drug Binding and Intracellular Signaling in the A_2A Adenosine Receptor

Cell. 2018 Jan 11;172(1-2):68-80.e12. doi: 10.1016/j.cell.2017.12.004. Epub 2017 Dec 28.

Authors

Affiliations

¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
² Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
³ Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA.
⁶ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: wuthrich@scripps.edu.

Abstract

Signaling across cellular membranes, the 826 human G protein-coupled receptors (GPCRs) govern a wide range of vital physiological processes, making GPCRs prominent drug targets. X-ray crystallography provided GPCR molecular architectures, which also revealed the need for additional structural dynamics data to support drug development. Here, nuclear magnetic resonance (NMR) spectroscopy with the wild-type-like A_2A adenosine receptor (A_2AAR) in solution provides a comprehensive characterization of signaling-related structural dynamics. All six tryptophan indole and eight glycine backbone ¹⁵N-¹H NMR signals in A_2AAR were individually assigned. These NMR probes provided insight into the role of Asp52^2.50 as an allosteric link between the orthosteric drug binding site and the intracellular signaling surface, revealing strong interactions with the toggle switch Trp 246^6.48, and delineated the structural response to variable efficacy of bound drugs across A_2AAR. The present data support GPCR signaling based on dynamic interactions between two semi-independent subdomains connected by an allosteric switch at Asp52^2.50.

Keywords: G protein-coupled receptor; GPCR; NMR; allosteric modulation; membrane protein; nuclear magnetic resonance; signaling.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine A2 Receptor Agonists / chemistry
Adenosine A2 Receptor Agonists / pharmacology
Allosteric Regulation*
Allosteric Site
Animals
Molecular Docking Simulation
Pichia
Protein Binding
Receptor, Adenosine A2A / chemistry*
Receptor, Adenosine A2A / metabolism
Sf9 Cells
Signal Transduction*
Spodoptera

Substances

Adenosine A2 Receptor Agonists
Receptor, Adenosine A2A

Abstract

Publication types

MeSH terms

Substances

Grants and funding