4os2

Crystal structure of urokinase-type plasminogen activator (uPA) complexed with bicyclic peptide UK602 (bicyclic 1)

spinqualitylabelsall models 4os2, resolution 1.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4os2 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, SO4 NonStd Res: 81S, NH2 Related: 4gly, 4os1, 4os4, 4os5, 4os6, 4os7 Activity: U-plasminogen activator, with EC number 3.4.21.73 Resources: FirstGlance, OCA, RCSB, PDBsum Disease [UROK_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. Function [UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. Publication Abstract from PubMed The disulfide bonds that form between two cysteine residues are important in defining and rigidifying the structures of proteins and peptides. In polypeptides containing multiple cysteine residues, disulfide isomerization can lead to multiple products with different biological activities. Here, we describe the development of a dithiol amino acid (Dtaa) that can form two disulfide bridges at a single amino acid site. Application of Dtaas to a serine protease inhibitor and a nicotinic acetylcholine receptor inhibitor that contain disulfide constraints enhanced their inhibitory activities 40- and 7.6-fold, respectively. X-ray crystallographic and NMR structure analysis show that the peptide ligands containing Dtaas have retained their native tertiary structures. We furthermore show that replacement of two cysteines by Dtaas can avoid the formation of disulfide bond isomers. With these properties, Dtaas are likely to have broad application in the rational design or directed evolution of peptides and proteins with high activity and stability. Dithiol amino acids can structurally shape and enhance the ligand-binding properties of polypeptides.,Chen S, Gopalakrishnan R, Schaer T, Marger F, Hovius R, Bertrand D, Pojer F, Heinis C Nat Chem. 2014 Nov;6(11):1009-16. doi: 10.1038/nchem.2043. Epub 2014 Aug 31. PMID:25343607 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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