7JQD

Crystal Structure of PAC1r in complex with peptide antagonist

Summary for 7JQD

• Entry DOI: 10.2210/pdb7jqd/pdb
• Descriptor: Pituitary adenylate cyclase-activating polypeptide type I receptor, Peptide-43 (3 entities in total)
• Functional Keywords: ecd, complex, antagonist, gpcr, signaling protein-antagonist complex, signaling protein/antagonist
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 16248.37

Authors

Piper, D.E.,Hu, E.,Fang-Tsao, H. (deposition date: 2020-08-10, release date: 2021-03-24, Last modification date: 2024-11-20)

Primary citation

Hu, E.,Hong, F.T.,Aral, J.,Long, J.,Piper, D.E.,Poppe, L.,Andrews, K.L.,Hager, T.,Davis, C.,Li, H.,Wong, P.,Gavva, N.,Shi, L.,Zhu, D.X.D.,Lehto, S.G.,Xu, C.,Miranda, L.P.
Discovery of Selective Pituitary Adenylate Cyclase 1 Receptor (PAC1R) Antagonist Peptides Potent in a Maxadilan/PACAP38-Induced Increase in Blood Flow Pharmacodynamic Model.
J.Med.Chem., 64:3427-3438, 2021

PubMed Abstract: Inhibition of the pituitary adenylate cyclase 1 receptor (PAC1R) is a novel mechanism that could be used for abortive treatment of acute migraine. Our research began with comparative analysis of known PAC1R ligand scaffolds, PACAP38 and Maxadilan, which resulted in the selection of des(24-42) Maxadilan, , as a starting point. C-terminal modifications of improved the peptide metabolic stability and . SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the PAC1R inhibitory activity of the analogs to the pM IC range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs and exhibited robust efficacy in the rat Maxadilan-induced increase in blood flow (MIIBF) pharmacodynamic model at 0.3 mg/kg subcutaneous dosing. The first cocrystal structure of a PAC1R antagonist peptide () with PAC1R extracellular domain is reported.

PubMed: 33715378
DOI: 10.1021/acs.jmedchem.0c01396

Experimental method

X-RAY DIFFRACTION (2.7 Å)