Structural Basis for Apelin Control of the Human Apelin Receptor

被引：98

作者：

Ma, Yingli ^{[1
]}

Yue, Yang ^{[2
]}

Ma, Yanbin ^{[1
]}

Zhang, Qing ^{[1
]}

Zhou, Qingtong ^{[2
]}

Song, Yunpeng ^{[1
]}

Shen, Yuqing ^{[1
]}

Li, Xun ^{[1
]}

Ma, Xiaochuan ^{[1
]}

Li, Chao ^{[2
,3
,4
,5
]}

Hanson, Michael A. ^{[6
]}

Han, Gye Won ^{[7
]}

Sickmier, E. Allen ^{[8
]}

Swaminath, Gayathri ^{[9
]}

Zhao, Suwen ^{[2
,3
]}

Stevens, Raymond C. ^{[2
,3
]}

Hu, Liaoyuan A. ^{[1
]}

Zhong, Wenge ^{[1
]}

Zhang, Mingqiang ^{[1
]}

Xu, Fei ^{[2
,3
]}

机构：

[1] Amgen Biopharmaceut R&D Shanghai Co Ltd, Amgen Asia R&D Ctr, Shanghai 201210, Peoples R China

[2] ShanghaiTech Univ, iHuman Inst, 2F Bldg 6,99 Haike Rd, Shanghai 201210, Peoples R China

[3] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

[4] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China

[5] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[6] GPCR Consortium, San Marcos, CA 92078 USA

[7] Univ Southern Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA

[8] Amgen Inc, Dept Mol Engn, Therapeut Discovery, 360 BinneySt, Cambridge, MA 02142 USA

[9] Amgen Inc, Cardiovasc Disorders, 1120 Vet Blvd, San Francisco, CA 94080 USA

来源：

STRUCTURE | 2017年 / 25卷 / 06期

基金：

上海市自然科学基金; 中国国家自然科学基金;

关键词：

PROTEIN-COUPLED RECEPTORS; KAPPA-OPIOID RECEPTOR; IMMUNODEFICIENCY-VIRUS TYPE-1; A(2A) ADENOSINE RECEPTOR; CRYSTALLIZING MEMBRANE; ANGIOTENSIN RECEPTOR; LIPIDIC MESOPHASES; HEART-FAILURE; AMINO-ACIDS; APJ;

D O I：

10.1016/j.str.2017.04.008

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Apelin receptor (APJR) is a key regulator of human cardiovascular function and is activated by two different endogenous peptide ligands, apelin and Elabela, each with different isoforms diversified by length and amino acid sequence. Here we report the 2.6-A resolution crystal structure of human APJR in complex with a designed 17-amino-acid apelin mimetic peptide agonist. The structure reveals that the peptide agonist adopts a lactam constrained curved two-site ligand binding mode. Combined with mutation analysis and molecular dynamics simulations with apelin-13 binding to the wild-type APJR, this structure provides a mechanistic understanding of apelin recognition and binding specificity. Comparison of this structure with that of other peptide receptors suggests that endogenous peptide ligands with a high degree of conformational flexibility may bind and modulate the receptors via a similar two site binding mechanism.

引用

页码：858 / +

页数：13

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