Crystal structure of the GLP-1 receptor bound to a peptide agonist

被引：143

作者：

Jazayeri, Ali ^{[1
]}

Rappas, Mathieu ^{[1
]}

Brown, Alastair J. H. ^{[1
]}

Kean, James ^{[1
]}

Errey, James C. ^{[1
]}

Robertson, Nathan J. ^{[1
]}

Fiez-Vandal, Cedric ^{[1
]}

Andrews, Stephen P. ^{[1
]}

Congreve, Miles ^{[1
]}

Bortolato, Andrea ^{[1
]}

Mason, Jonathan S. ^{[1
]}

Baig, Asma H. ^{[1
]}

Teobald, Iryna ^{[1
]}

Dore, Andrew S. ^{[1
]}

Weir, Malcolm ^{[1
]}

Cooke, Robert M. ^{[1
]}

Marshall, Fiona H. ^{[1
]}

机构：

[1] Heptares Therapeut Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England

来源：

NATURE | 2017年 / 546卷 / 7657期

关键词：

GLUCAGON-LIKE PEPTIDE-1; LIGAND-BINDING; DEGRADATION; REFINEMENT; ACTIVATION; RESIDUES; FEATURES; FAMILY; DOMAIN;

D O I：

10.1038/nature22800

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an a-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.

引用

页码：254 / +

页数：17

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