7jqd
From Proteopedia
Crystal Structure of PAC1r in complex with peptide antagonist
Structural highlights
FunctionPACR_HUMAN This is a receptor for PACAP-27 and PACAP-38. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. May regulate the release of adrenocorticotropin, luteinizing hormone, growth hormone, prolactin, epinephrine, and catecholamine. May play a role in spermatogenesis and sperm motility. Causes smooth muscle relaxation and secretion in the gastrointestinal tract. Publication Abstract from PubMedInhibition 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, 6, as a starting point. C-terminal modifications of 6 improved the peptide metabolic stability in vitro and in vivo. SAR investigations identified synergistic combinations of amino acid replacements that significantly increased the in vitro PAC1R inhibitory activity of the analogs to the pM IC(90) range. Our modifications further enabled deletion of up to six residues without impacting potency, thus improving peptide ligand binding efficiency. Analogs 17 and 18 exhibited robust in vivo 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 (18) with PAC1R extracellular domain is reported. Discovery of Selective Pituitary Adenylate Cyclase 1 Receptor (PAC1R) Antagonist Peptides Potent in a Maxadilan/PACAP38-Induced Increase in Blood Flow Pharmacodynamic Model.,Hu E, Hong FT, Aral J, Long J, Piper DE, Poppe L, Andrews KL, Hager T, Davis C, Li H, Wong P, Gavva N, Shi L, Zhu DXD, Lehto SG, Xu C, Miranda LP J Med Chem. 2021 Mar 25;64(6):3427-3438. doi: 10.1021/acs.jmedchem.0c01396. Epub , 2021 Mar 15. PMID:33715378[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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