The impact of cryo-EM on determining allosteric modulator-bound structures of G protein-coupled receptors

Liudi Zhang; Jesse I Mobbs; Lauren T May; Alisa Glukhova; David M Thal

doi:10.1016/j.sbi.2023.102560

The impact of cryo-EM on determining allosteric modulator-bound structures of G protein-coupled receptors

Curr Opin Struct Biol. 2023 Apr:79:102560. doi: 10.1016/j.sbi.2023.102560. Epub 2023 Feb 26.

Authors

Liudi Zhang¹, Jesse I Mobbs², Lauren T May³, Alisa Glukhova⁴, David M Thal⁵

Affiliations

¹ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia.
² Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia. Electronic address: https://twitter.com/@JesseMobbs.
³ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia. Electronic address: https://twitter.com/@laurentmay.
⁴ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria 3010, Australia. Electronic address: https://twitter.com/@gl_alisa.
⁵ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria Australia. Electronic address: david.thal@monash.edu.

PMID: 36848776
DOI: 10.1016/j.sbi.2023.102560

Abstract

G-protein coupled receptors (GPCRs) are important therapeutic targets for the treatment of human disease. Although GPCRs are highly successful drug targets, there are many challenges associated with the discovery and translation of small molecule ligands that target the endogenous ligand-binding site for GPCRs. Allosteric modulators are a class of ligands that target alternative binding sites known as allosteric sites and offer fresh opportunities for the development of new therapeutics. However, only a few allosteric modulators have been approved as drugs. Advances in GPCR structural biology enabled by the cryogenic electron microscopy (cryo-EM) revolution have provided new insights into the molecular mechanism and binding location of small molecule allosteric modulators. This review highlights the latest findings from allosteric modulator-bound structures of Class A, B, and C GPCRs with a focus on small molecule ligands. Emerging methods that will facilitate cryo-EM structures of more difficult ligand-bound GPCR complexes are also discussed. The results of these studies are anticipated to aid future structure-based drug discovery efforts across many different GPCRs.

Keywords: Allostery; Cryo-EM; Drug discovery; G protein-coupled receptors.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation* / drug effects
Allosteric Site / drug effects
Animals
Cryoelectron Microscopy*
Humans
Lipid Bilayers / chemistry
Lipid Bilayers / metabolism
Membrane Lipids / chemistry
Membrane Lipids / metabolism
Protein Conformation / drug effects
Receptors, G-Protein-Coupled* / chemistry
Receptors, G-Protein-Coupled* / classification
Receptors, G-Protein-Coupled* / metabolism
Receptors, G-Protein-Coupled* / ultrastructure

Substances

Lipid Bilayers
Membrane Lipids
Receptors, G-Protein-Coupled