Theoretical identification of thermostabilizing amino acid mutations for G-protein-coupled receptors

被引：4

作者：

Murata T. ^{[1
,2
]}

Yasuda S. ^{[1
,2
,3
]}

Hayashi T. ^{[3
,4
]}

Kinoshita M. ^{[3
]}

机构：

[1] Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba

[2] Molecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, Inage, Chiba

[3] Institute of Advanced Energy, Kyoto University, Uji, Kyoto

[4] Present address: Interdisciplinary Program of Biomedical Engineering, Assistive Technology, and Art and Sports Sciences, Faculty of Engineering, Niigata University, 8050 Ikarashi 2-no-cho, Nishi-ku, Niigata

来源：

Biophysical Reviews | 2020年 / 12卷 / 2期

基金：

日本学术振兴会;

关键词：

G-protein-coupled receptor; Integral equation theory; Lipid bilayer; Membrane protein; Morphometric approach; Protein folding; Solvation thermodynamics; Thermostabilizing mutation;

D O I：

10.1007/s12551-020-00678-5

中图分类号：

学科分类号：

摘要：

Thermostabilization of a membrane proteins, especially G-protein-coupled receptors (GPCRs), is often necessary for biochemical applications and pharmaceutical studies involving structure-based drug design. Here we review our theoretical, physics-based method for identifying thermostabilizing amino acid mutations. Its novel aspects are the following: The entropic effect originating from the translational displacement of hydrocarbon groups within the lipid bilayer is treated as a pivotal factor; a reliable measure of thermostability is introduced and a mutation which enlarges the measure to a significant extent is chosen; and all the possible mutations can be examined with moderate computational effort. It was shown that mutating the residue at a position of NBW = 3.39 (NBW is the Ballesteros-Weinstein number) to Arg or Lys leads to the stabilization of significantly many different GPCRs of class A in the inactive state. Up to now, we have been successful in stabilizing several GPCRs and newly solving three-dimensional structures for the muscarinic acetylcholine receptor 2 (M2R), prostaglandin E receptor 4 (EP4), and serotonin 2A receptor (5-HT2AR) using X-ray crystallography. The subjects to be pursued in future studies are also discussed. © 2020, International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature.

引用

页码：323 / 332

页数：9

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