Computational design of thermostabilizing point mutations for G protein-coupled receptors

doi:10.7554/eLife.34729

KMS > iHuman研究所

	Computational design of thermostabilizing point mutations for G protein-coupled receptors
	Popov, Petr 1,2; Peng, Yao3 ; Shen, Ling3,4 ; Stevens, Raymond C.1,3,5,6 ; Cherezov, Vadim 1,2,5,6; Liu, Zhi-Jie3,4,7 ; Katritch, Vsevolod 1,2,5,6
	2018-06-21
发表期刊	ELIFE (IF:6.4[JCR-2023],7.2[5-Year])
ISSN	2050-084X
卷号	7
发表状态	已发表
DOI	10.7554/eLife.34729
摘要	Engineering of GPCR constructs with improved thermostability is a key for successful structural and biochemical studies of this transmembrane protein family, targeted by 40% of all therapeutic drugs. Here we introduce a comprehensive computational approach to effective prediction of stabilizing mutations in GPCRs, named CompoMug, which employs sequence-based analysis, structural information, and a derived machine learning predictor. Tested experimentally on the serotonin 5-HT2c receptor target, CompoMug predictions resulted in 10 new stabilizing mutations, with an apparent thermostability gain similar to 8.8 degrees C for the best single mutation and similar to 13 degrees C for a triple mutant. Binding of antagonists confers further stabilization for the triple mutant receptor, with total gains of similar to 21 degrees C as compared to wild type apo 5-HT2c. The predicted mutations enabled crystallization and structure determination for the 5-HT2c receptor complexes in inactive and active-like states. While CompoMug already shows high 25% hit rate and utility in GPCR structural studies, further improvements are expected with accumulation of structural and mutation data.
收录类别	SCI ; SCIE
语种	英语
资助项目	Ministry of Science and Technology of China[2014CB910400] ; Ministry of Science and Technology of China[2015CB910104]
WOS研究方向	Life Sciences & Biomedicine - Other Topics
WOS类目	Biology
WOS记录号	WOS:000435892300001
出版者	ELIFE SCIENCES PUBLICATIONS LTD
WOS关键词	ADENOSINE A(2A) RECEPTOR ; BETA(1)-ADRENERGIC RECEPTOR ; STRUCTURAL BASIS ; ALLOSTERIC SODIUM ; DRUG DISCOVERY ; GPCR STRUCTURE ; STABILITY ; CRYSTALLIZATION ; IDENTIFICATION ; CONFORMATIONS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/27452
专题	iHuman研究所生命科学与技术学院 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_PI研究组_刘志杰组生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Katritch, Vsevolod
作者单位	1.Univ Southern Calif, Dept Biol Sci, Los Angeles, CA 90089 USA 2.Moscow Inst Phys & Technol, Dolgoprudnyi, Russia 3.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 5.Univ Southern Calif, Dept Chem, Los Angeles, CA 90089 USA 6.Univ Southern Calif, Bridge Inst, Los Angeles, CA USA 7.Kunming Med Univ, Insititute Mol & Clin Med, Kunming, Yunnan, Peoples R China
推荐引用方式 GB/T 7714	Popov, Petr,Peng, Yao,Shen, Ling,et al. Computational design of thermostabilizing point mutations for G protein-coupled receptors[J]. ELIFE,2018,7.
APA	Popov, Petr.,Peng, Yao.,Shen, Ling.,Stevens, Raymond C..,Cherezov, Vadim.,...&Katritch, Vsevolod.(2018).Computational design of thermostabilizing point mutations for G protein-coupled receptors.ELIFE,7.
MLA	Popov, Petr,et al."Computational design of thermostabilizing point mutations for G protein-coupled receptors".ELIFE 7(2018).