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Annu Rev Pharmacol Toxicol. 2019 Jul 26. doi: 10.1146/annurev-pharmtox-010919-023545. [Epub ahead of print]

Cryo-Electron Microscopy: Moving Beyond X-Ray Crystal Structures for Drug Receptors and Drug Development.

Author information

1
MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; email: cgt@mrc-lmb.cam.ac.uk, jgarcia@mrc-lmb.cam.ac.uk.
2
Current affiliation: Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, 50018 Zaragoza, Spain.

Abstract

Electron cryo-microscopy (cryo-EM) has revolutionized structure determination of membrane proteins and holds great potential for structure-based drug discovery. Here we discuss the potential of cryo-EM in the rational design of therapeutics for membrane proteins compared to X-ray crystallography. We also detail recent progress in the field of drug receptors, focusing on cryo-EM of two protein families with established therapeutic value, the γ-aminobutyric acid A receptors (GABAARs) and G protein-coupled receptors (GPCRs). GABAARs are pentameric ion channels, and cryo-EM structures of physiological heteromeric receptors in a lipid environment have uncovered the molecular basis of receptor modulation by drugs such as diazepam. The structures of ten GPCR-G protein complexes from three different classes of GPCRs have now been determined by cryo-EM. These structures give detailed insights into molecular interactions with drugs, GPCR-G protein selectivity, how accessory membrane proteins alter receptor-ligand pharmacology, and the mechanism by which HIV uses GPCRs to enter host cells. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 60 is January 9, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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