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Structure. 2017 Jun 6;25(6):858-866.e4. doi: 10.1016/j.str.2017.04.008. Epub 2017 May 18.

Structural Basis for Apelin Control of the Human Apelin Receptor.

Author information

1
Amgen Asia R&D Center, Amgen Biopharmaceutical R&D (Shanghai) Co., Ltd, Shanghai 201210, China.
2
iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China.
3
iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
4
GPCR Consortium, San Marcos, CA 92078, USA.
5
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
6
Therapeutic Discovery, Department of Molecular Engineering, Amgen Inc., 360 BinneyStreet, Cambridge, MA 02142, USA.
7
Cardiovascular Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
8
iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
9
iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: xufei@shanghaitech.edu.cn.

Abstract

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-Å 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.

KEYWORDS:

apelin recognition and binding specificity; cardiovascular drug target; designed agonist peptide mimic; human apelin receptor

PMID:
28528775
DOI:
10.1016/j.str.2017.04.008
[Indexed for MEDLINE]
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