5OTX

Extracellular domain of GLP-1 receptor in complex with GLP-1 variant Ala8Cys/Thr11Cys

Summary for 5OTX

• Entry DOI: 10.2210/pdb5otx/pdb
• Descriptor: Glucagon-like peptide 1 receptor, Glucagon (3 entities in total)
• Functional Keywords: glucagon-like peptide 1, gpcr, cyclic peptides, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 33883.39

Authors

Mortensen, S. (deposition date: 2017-08-22, release date: 2018-07-04, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)