PDBsum entry 3c5t

Signaling protein/signaling protein

PDB id: 3c5t

Contents

Protein chains

104 a.a. *

25 a.a. *

Ligands

10M

Waters ×126

* Residue conservation analysis

PDB id:

3c5t

Name:

Signaling protein/signaling protein

Title:

Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain

Structure:

Glucagon-like peptide 1 receptor. Chain: a. Fragment: n-terminal extracellular domain, unp residues 24-145. Synonym: glp-1 receptor, glp-1-r, glp-1r. Engineered: yes. Exendin-4. Chain: b. Fragment: unp residues 56-86. Synonym: exenatide.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: glucagon-like peptide-1 receptor(glp1r). Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: exendin-4(9-39) was generated by chemical synthesis. This sequence occurs naturally in heloderma suspectum.

Resolution:

2.10Å R-factor: 0.205 R-free: 0.238

Authors:

S.Runge

Key ref:

S.Runge et al. (2008). Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain. J Biol Chem, 283, 11340-11347. PubMed id: 18287102 DOI: 10.1074/jbc.M708740200

Date:

01-Feb-08 Release date: 19-Feb-08

Protein chain

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

Seq: 463 a.a.

Struc: 104 a.a.

Protein chain

P26349  (EXE4_HELSU) -  Exendin-4 from Heloderma suspectum

Seq: 87 a.a.

Struc: 25 a.a.

DOI no: 10.1074/jbc.M708740200

J Biol Chem 283:11340-11347 (2008)

PubMed id: 18287102

Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain.

S.Runge, H.Thøgersen, K.Madsen, J.Lau, R.Rudolph.

ABSTRACT

The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B1 of the seven-transmembrane G protein-coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is involved in glucose homeostasis, and activation of GLP-1R in the plasma membrane of pancreatic beta-cells potentiates glucose-dependent insulin secretion. The N-terminal extracellular domain (nGLP-1R) is an important ligand binding domain that binds GLP-1 and the homologous peptide Exendin-4 with differential affinity. Exendin-4 has a C-terminal extension of nine amino acid residues known as the "Trp cage", which is absent in GLP-1. The Trp cage was believed to interact with nGLP-1R and thereby explain the superior affinity of Exendin-4. However, the molecular details that govern ligand binding and specificity of nGLP-1R remain undefined. Here we report the crystal structure of human nGLP-1R in complex with the antagonist Exendin-4(9-39) solved by the multiwavelength anomalous dispersion method to 2.2A resolution. The structure reveals that Exendin-4(9-39) is an amphipathic alpha-helix forming both hydrophobic and hydrophilic interactions with nGLP-1R. The Trp cage of Exendin-4 is not involved in binding to nGLP-1R. The hydrophobic binding site of nGLP-1R is defined by discontinuous segments including primarily a well defined alpha-helix in the N terminus of nGLP-1R and a loop between two antiparallel beta-strands. The structure provides for the first time detailed molecular insight into ligand binding of the human GLP-1 receptor, an established target for treatment of type 2 diabetes.

Selected figure(s)

Figure 3.
FIGURE 3. Superposition of the solution NMR structure of Ex4 in TFE (Protein Data Bank code 1JRJ) and the receptor-bound crystal structure of Ex4(9–39). The surface of nGLP-1R is illustrated in gray, highlighting the hydrophobic binding cavity in magenta. The secondary structure of receptor-bound Ex4(9–39) is illustrated in blue. The side chains of Glu^15*, Val^19*, Phe^22*, Ile^23*, Trp^25*, Leu^26*, Pro^31*, and Ser^32*, of receptor-bound Ex4(9–39) and Ex4 in solution are shown in blue and yellow sticks, respectively.

Figure 4.
FIGURE 4. Superposition of ligand-bound nPAC1, nCRF-R2B, nGIPR, and nGLP-1R. The conserved core structures of the Nt-domains were aligned by superposition of the ligand-bound structures using PyMOL. A surface representation of nGLP-1R is shown in gray, and the ligands are illustrated by ribbon diagrams, Ex4(9–39) in blue, GIP(1–42) in magenta, astressin in yellow, and PACAP(6–38) in red.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 11340-11347) copyright 2008.

Figures were selected by an automated process.