5OTW

Extracellular domain of GLP-1 receptor in complex with GLP-1 variant Ala8Hcs/Thr11Cys

5OTW の概要

• エントリーDOI: 10.2210/pdb5otw/pdb
• 分子名称: Glucagon-like peptide 1 receptor, Glucagon (3 entities in total)
• 機能のキーワード: glucagon-like peptide 1, gpcr, cyclic peptides, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 33911.44

構造登録者

Mortensen, S. (登録日: 2017-08-22, 公開日: 2018-07-04, 最終更新日: 2024-10-16)

主引用文献

Oddo, A.,Mortensen, S.,Thogersen, H.,De Maria, L.,Hennen, S.,McGuire, J.N.,Kofoed, J.,Linderoth, L.,Reedtz-Runge, S.
alpha-Helix or beta-Turn? An Investigation into N-Terminally Constrained Analogues of Glucagon-like Peptide 1 (GLP-1) and Exendin-4.
Biochemistry, 57:4148-4154, 2018

PubMed Abstract: Peptide agonists acting on the glucagon-like peptide 1 receptor (GLP-1R) promote glucose-dependent insulin release and therefore represent important therapeutic agents for type 2 diabetes (T2D). Previous data indicated that an N-terminal type II β-turn motif might be an important feature for agonists acting on the GLP-1R. In contrast, recent publications reporting the structure of the full-length GLP-1R have shown the N-terminus of receptor-bound agonists in an α-helical conformation. To reconcile these conflicting results, we prepared N-terminally constrained analogues of glucagon-like peptide 1 (GLP-1) and exendin-4 and evaluated their receptor affinity and functionality in vitro; we then examined their crystal structures in complex with the extracellular domain of the GLP-1R and used molecular modeling and molecular dynamics simulations for further investigations. We report that the peptides' N-termini in all determined crystal structures adopted a type II β-turn conformation, but in vitro potency varied several thousand-fold across the series. Potency correlated better with α-helicity in our computational model, although we have found that the energy barrier between the two mentioned conformations is low in our most potent analogues and the flexibility of the N-terminus is highlighted by the dynamics simulations.

PubMed: 29877701
DOI: 10.1021/acs.biochem.8b00105

実験手法

X-RAY DIFFRACTION (2.1 Å)