4ZGM

Crystal structure of Semaglutide peptide backbone in complex with the GLP-1 receptor extracellular domain

Summary for 4ZGM

• Entry DOI: 10.2210/pdb4zgm/pdb
• Related: 3IOL
• Descriptor: Glucagon-like peptide 1 receptor, Semaglutide peptide backbone; 8Aib,34R-GLP-1(7-37)-OH, 3,6,9,12,15,18-hexaoxahexacosan-1-ol, ... (4 entities in total)
• Functional Keywords: glp-1, receptor, complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P43220
• Total number of polymer chains: 2
• Total formula weight: 18516.67

Authors

Reedtz-Runge, S. (deposition date: 2015-04-23, release date: 2015-09-09, Last modification date: 2024-01-10)

Primary citation

Lau, J.,Bloch, P.,Schaffer, L.,Pettersson, I.,Spetzler, J.,Kofoed, J.,Madsen, K.,Knudsen, L.B.,McGuire, J.,Steensgaard, D.B.,Strauss, H.M.,Gram, D.X.,Knudsen, S.M.,Nielsen, F.S.,Thygesen, P.,Reedtz-Runge, S.,Kruse, T.
Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.
J.Med.Chem., 58:7370-7380, 2015

PubMed 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.

PubMed: 26308095
DOI: 10.1021/acs.jmedchem.5b00726

Experimental method

X-RAY DIFFRACTION (1.8 Å)