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Protein Design Strategies for the Structural–Functional Studies of G Protein-Coupled Receptors

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Abstract

G protein-coupled receptors (GPCRs) are an important family of membrane proteins responsible for many physiological functions in human body. High resolution GPCR structures are required to understand their molecular mechanisms and perform rational drug design, as GPCRs play a crucial role in a variety of diseases. That is difficult to obtain for the wild-type proteins because of their low stability. In this review, we discuss how this problem can be solved by using protein design strategies developed to obtain homogeneous stabilized GPCR samples for crystallization and cryoelectron microscopy.

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Abbreviations

BRIL:

thermostabilized apocytochrome b562

cryo-EM:

cryoelectron microscopy

GDP:

guanosine diphosphate

GPCR:

G protein-coupled receptor

GPCRdb:

database containing information on modern studies of GPCR (https://gpcrdb.org/)

GRK:

G protein-coupled receptor kinase

LCP:

lipid cubic phase

MBP:

maltose-binding protein

Nb:

nanobody

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Funding

Review of Membrane model systems in GPCR studies were supported by the Ministry of Science and Higher Education of the Russian Federation (agreement 075-03-2023-106, project FSMG-2020-0003). Review of Characterization of Protein Preparations and Quality Control was supported by the Russian Science Foundation (project no. 22-74-00024, https://rscf.ru/project/22-74-00024/ [in Russian]). Other parts of the work were supported by the Russian Science Foundation (project no. 22-74-10036; https://rscf.ru/project/22-74-10036/ [in Russian]).

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  1. Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141701, Dolgoprudny, Moscow Region, Russia

    Daria A. Dmitrieva, Tatiana V. Kotova, Nadezda A. Safronova, Alexandra A. Sadova, Dmitrii E. Dashevskii & Alexey V. Mishin

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Daria A. Dmitrieva was responsible for the “Introduction of Point Mutations”, “Alanine Scanning and StaR™ Technology”, “Directed Evolution”, “Use of Fusion Partners”, “Expression Systems for GPCR Production”, “Using Ligands for Receptor Stabilization”, “Using Antibody Fragments for Stabilization of GPCR Conformational States” sections. Tatiana V. Kotova was responsible for the “Introduction of Point Mutations”, “Alanine Scanning and StaR™ Technology” sections (with D.A.D.), “Deletion of Unordered Regions from the Receptor Amino Acid Sequence”, “Insertion of Additional Elements into the Receptor Amino Acid Sequence”, “Methods for GPCR Purification”, “Formation of Receptor Complexes with Main Interaction Partners” sections. Nadezda A. Safronova authored the “Using Salts and Chemical Agents for Purification and Stabilization of Receptors” section. Alexandra A. Sadova was responsible for the “Membrane Model Systems in GPCR Studies; Their Pros and Cons” section. Dmitrii E. Dashevskii wrote the “Characterization of Protein Preparations and Quality Control” section. Alexey V. Mishin authored the conception and the initial plan of the review, edited the whole manuscript.

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Correspondence to Alexey V. Mishin.

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The authors declare no conflict of interest in financial or any other sphere.

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Translated from Uspekhi Biologicheskoi Khimii, 2023, Vol. 63, pp. 379-448.

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Dmitrieva, D.A., Kotova, T.V., Safronova, N.A. et al. Protein Design Strategies for the Structural–Functional Studies of G Protein-Coupled Receptors. Biochemistry Moscow 88 (Suppl 1), S192–S226 (2023). https://doi.org/10.1134/S0006297923140110

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  • DOI: https://doi.org/10.1134/S0006297923140110

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