6GB1

Crystal structure of the GLP1 receptor ECD with Peptide 11

Summary for 6GB1

• Entry DOI: 10.2210/pdb6gb1/pdb
• Descriptor: Glucagon-like peptide 1 receptor, Peptide 11, SULFATE ION, ... (5 entities in total)
• Functional Keywords: glucagon-like peptide 1 protein-peptide complex incretins diabetes drug discovery, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 18505.53

Authors

Schreuder, H.A.,Liesum, A. (deposition date: 2018-04-13, release date: 2018-06-20, Last modification date: 2024-01-17)

Primary citation

Evers, A.,Bossart, M.,Pfeiffer-Marek, S.,Elvert, R.,Schreuder, H.,Kurz, M.,Stengelin, S.,Lorenz, M.,Herling, A.,Konkar, A.,Lukasczyk, U.,Pfenninger, A.,Lorenz, K.,Haack, T.,Kadereit, D.,Wagner, M.
Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists Specifically Optimized for Multidose Formulations.
J. Med. Chem., 61:5580-5593, 2018

PubMed Abstract: Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 receptor agonists with regard to treatment of obesity and diabetes. We describe novel exendin-4 based dual agonists designed with an activity ratio favoring the GLP-1 versus the glucagon receptor. As result of an iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), peptide design and synthesis, experimental activity, and solubility profiling, a candidate molecule was identified. Novel SAR points are reported that allowed us to fine-tune the desired receptor activity ratio and increased solubility in the presence of antimicrobial preservatives, findings that can be of general applicability for any peptide discovery project. The peptide was evaluated in chronic in vivo studies in obese diabetic monkeys as translational model for the human situation and demonstrated favorable blood glucose and body weight lowering effects.

PubMed: 29879354
DOI: 10.1021/acs.jmedchem.8b00292

Experimental method

X-RAY DIFFRACTION (2.73 Å)