PDBsum entry 4zgm

Signaling protein

PDB id: 4zgm

Contents

Protein chains

100 a.a.

28 a.a.

Ligands

32M ×2

Waters ×88

PDB id:

4zgm

Name:

Signaling protein

Title:

Crystal structure of semaglutide peptide backbone in complex with the glp-1 receptor extracellular domain

Structure:

Glucagon-like peptide 1 receptor. Chain: a. Synonym: glp-1r. Engineered: yes. Semaglutide peptide backbone. 8aib,34r-glp-1(7-37)-oh. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: glp1r. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.80Å R-factor: 0.164 R-free: 0.193

Authors:

S.Reedtz-Runge

Key ref:

J.Lau et al. (2015). Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem, 58, 7370-7380. PubMed id: 26308095 DOI: 10.1021/acs.jmedchem.5b00726

Date:

23-Apr-15 Release date: 09-Sep-15

Protein chain

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

Seq: 463 a.a.

Struc: 100 a.a.

Protein chain

P01275  (GLUC_HUMAN) -  Pro-glucagon from Homo sapiens

Seq: 180 a.a.

Struc: 28 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.?

DOI no: 10.1021/acs.jmedchem.5b00726

J Med Chem 58:7370-7380 (2015)

PubMed id: 26308095

Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.

J.Lau, P.Bloch, L.Schäffer, I.Pettersson, J.Spetzler, J.Kofoed, K.Madsen, L.B.Knudsen, J.McGuire, D.B.Steensgaard, H.M.Strauss, D.X.Gram, S.M.Knudsen, F.S.Nielsen, P.Thygesen, S.Reedtz-Runge, T.Kruse.

ABSTRACT

Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib(8), Arg(34)) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clinical testing.