PDBsum entry 5vex

Signaling protein

PDB id: 5vex

Contents

Protein chains

423 a.a.

Ligands

97V ×2

PDB id:

5vex

Name:

Signaling protein

Title:

Structure of the human glp-1 receptor complex with nnc0640

Structure:

Glucagon-like peptide 1 receptor, endolysin chimera. Chain: a, b. Synonym: glp-1r,lysis protein,lysozyme,muramidase. Engineered: yes

Source:

Homo sapiens, enterobacteria phage t4. Human. Organism_taxid: 9606, 10665. Gene: glp1r. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

3.00Å R-factor: 0.234 R-free: 0.256

Authors:

G.Song,D.Yang,Y.Wang,C.D.Graaf,Q.Zhou,S.Jiang,K.Liu,X.Cai,A.Dai, G.Lin,D.Liu,F.Wu,Y.Wu,S.Zhao,L.Ye,G.W.Han,J.Lau,B.Wu,M.A.Hanson,Z.- J.Liu,M.-W.Wang,R.C.Stevens

Key ref:

G.Song et al. (2017). Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature, 546, 312-315. PubMed id: 28514449

Date:

05-Apr-17 Release date: 17-May-17

Protein chains

P00720  (ENLYS_BPT4) -  Endolysin from Enterobacteria phage T4

Seq: 164 a.a.

Struc: 423 a.a.*

Protein chains

P43220  (GLP1R_HUMAN) -  Glucagon-like peptide 1 receptor from Homo sapiens

Seq: 463 a.a.

Struc: 423 a.a.*

* PDB and UniProt seqs differ at 178 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.2.1.17 - lysozyme.
• Reaction: Hydrolysis of the 1,4-beta-linkages between N-acetyl-D-glucosamine and N-acetylmuramic acid in peptidoglycan heteropolymers of the prokaryotes cell walls.

Nature 546:312-315 (2017)

PubMed id: 28514449

Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators.

G.Song, D.Yang, Y.Wang, C.de Graaf, Q.Zhou, S.Jiang, K.Liu, X.Cai, A.Dai, G.Lin, D.Liu, F.Wu, Y.Wu, S.Zhao, L.Ye, G.W.Han, J.Lau, B.Wu, M.A.Hanson, Z.J.Liu, M.W.Wang, R.C.Stevens.

ABSTRACT

The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.