3qn7
From Proteopedia
Potent and selective bicyclic peptide inhibitor (UK18) of human urokinase-type plasminogen activator(uPA)
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 PubMedFrom a large combinatorial library of chemically constrained bicyclic peptides we isolated a selective and potent (K(i) = 53 nM) inhibitor of human urokinase-type plasminogen activator (uPA) and crystallized the complex. This revealed an extended structure of the peptide with both peptide loops engaging the target to form a large interaction surface of 701 A(2) with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics. Bicyclic peptide inhibitor reveals large contact interface with a protease target.,Angelini A, Cendron L, Chen S, Touati J, Winter G, Zanotti G, Heinis C ACS Chem Biol. 2012 May 18;7(5):817-21. doi: 10.1021/cb200478t. Epub 2012 Feb 15. PMID:22304751[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 | Angelini A | Cendron L | Heinis C | Touati J | Winter G | Zanotti G
