Crystal structure of a constitutive active mutant of adenosine A(2A) receptor
2022-05
发表期刊IUCRJ
ISSN2052-2525
卷号9
发表状态已发表
DOI10.1107/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
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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).
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