Crystal structure of a constitutive active mutant of adenosine A(2A) receptor

doi:10.1107/S2052252522001907

	Crystal structure of a constitutive active mutant of adenosine A(2A) receptor
	Cui, Min 1,2; Zhou, Qingtong 3; Xu, Yueming 1,2; Weng, Yuan 1,2; Yao, Deqiang 4; Zhao, Suwen5,6 ; Song, Gaojie 1,2
	2022-05
发表期刊	IUCRJ
ISSN	2052-2525
卷号	9
发表状态	已发表
DOI	10.1107/S2052252522001907
摘要	The adenosine A(2A) receptor (A(2A)AR) is a prototypical member of the class A subfamily of G-protein-coupled receptors (GPCRs) that is widely distributed in various tissues and organs of the human body, and participates in many important signal-regulation processes. We have previously summarized a common activation pathway of class A GPCRs in which a series of conserved residues/motifs undergo conformational change during extracellular agonist binding and finally induce the coupling of intracellular G protein. Through this mechanism we have successfully predicted several novel constitutive active or inactive mutations for A(2A)AR. To reveal the molecular mechanism of mutation-induced constitutive activity, we determined the structure of a typical mutant I92N complexed with the agonist UK-432097. The mutated I92N forms a hydrophilic interaction network with nearby residues including Trp(6.48) of the CWxP motif, which is absent in wild-type A(2A)AR. Although the mutant structure is similar overall to the previously determined intermediate-state A(2A)AR structure (PDB ID 3qak) [Xu, Wu, Katritch, Han, Jacobson, Gao, Cherezov & Stevens (2011). Science, 332, 322-327], molecular dynamics simulations suggest that the I92N mutant stabilizes the metastable intermediate state through the hydrophilic interaction network and favors the conformational transition of the receptor towards the active state. This research provides a structural template towards the special pharmacological outcome triggered by conformational mutation and sheds light on future structural or pharmacological studies among class A GPCRs.
关键词	constitutive active mutants adenosine A(2A) receptors crystal structures hydrophilic interaction networks molecular dynamics G-protein-coupled receptors agonists
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
资助项目	National Key Research and Development Program of China["2018YFA0507000","2018YFA0507001"] ; National Nature Science Foundation of China[31770898,21704064,31971178] ; National Science and Technology Major Project of China-Innovation 2030 for Brain Science and Brain-Inspired Technology[2021ZD0203400]
WOS研究方向	Chemistry ; Crystallography ; Materials Science
WOS类目	Chemistry, Multidisciplinary ; Crystallography ; Materials Science, Multidisciplinary
WOS记录号	WOS:000795859800003
出版者	INT UNION CRYSTALLOGRAPHY
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/185363
专题	生命科学与技术学院 iHuman研究所_PI研究组_赵素文组
通讯作者	Zhou, Qingtong; Song, Gaojie
作者单位	1.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China 2.East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China 3.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China 4.Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, State Key Lab Oncogenes & Related Genes, Shanghai 200127, Peoples R China 5.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Cui, Min,Zhou, Qingtong,Xu, Yueming,et al. Crystal structure of a constitutive active mutant of adenosine A(2A) receptor[J]. IUCRJ,2022,9.
APA	Cui, Min.,Zhou, Qingtong.,Xu, Yueming.,Weng, Yuan.,Yao, Deqiang.,...&Song, Gaojie.(2022).Crystal structure of a constitutive active mutant of adenosine A(2A) receptor.IUCRJ,9.
MLA	Cui, Min,et al."Crystal structure of a constitutive active mutant of adenosine A(2A) receptor".IUCRJ 9(2022).