6xvd
From Proteopedia
Crystal structure of complex of urokinase and a upain-1 variant(W3F) in pH7.4 condition
Structural highlights
DiseaseUROK_HUMAN Defects in PLAU are the cause of Quebec platelet disorder (QPD) [MIM:601709. QPD is an autosomal dominant bleeding disorder due to a gain-of-function defect in fibrinolysis. Although affected individuals do not exhibit systemic fibrinolysis, they show delayed onset bleeding after challenge, such as surgery. The hallmark of the disorder is markedly increased PLAU levels within platelets, which causes intraplatelet plasmin generation and secondary degradation of alpha-granule proteins.[1] FunctionUROK_HUMAN Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. Publication Abstract from PubMedPeptidic inhibitors of proteases are attracting increasing interest not only as drug candidates but also for studying the function and regulation mechanisms of these [Formula: see text] out a cyclic peptide inhibitor of human uPA (upain-1, CSWRGLENHRMC) and found that Ala substitution of P2 residue turns upain-1 to a substrate. To further investigate the effect of P2 residue on the peptide behavior transformation, we constructed upain-1-W3F, which has Phe replacement in the P2 position. We determined KD and Ki of upain-1-W3F and found that upain-1-W3F might still exist as an inhibitor. Furthermore, the high-resolution crystal structure of upain-1-W3F.uPA reveals that upain-1-W3F indeed stays as an intact inhibitor bind to uPA. We thus propose that the P2 residue plays a nonnegligible role in the conversion of upain-1 to a substrate. These results also proposed a strategy to optimize the pharmacological properties of peptide-based drug candidates by hydrophobicity and steric hindrance.Abbreviations : uPA: urokinase-type plasminogen activator; SPD: serine protease domain; S1 pocket: specific substrate-binding pocket. Insight to the residue in P2 position prevents the peptide inhibitor from being hydrolyzed by serine proteases.,Xue G, Xie X, Zhou Y, Yuan C, Huang M, Jiang L Biosci Biotechnol Biochem. 2020 Feb 5:1-7. doi: 10.1080/09168451.2020.1723405. PMID:32019421[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Synthetic construct | Huang MD | Jiang LG | Xie X | Xue GP | Yuan C | Zhou Y
