4jk6

Human urokinase-type Plasminogen Activator (uPA) in complex with a bicyclic peptide inhibitor (UK18-D-Aba)

spinqualitylabelsall models 4jk6, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4jk6 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, P6G, SO4, ZBR NonStd Res: DBB, NH2 Related: 4gly, 3qn7 Gene: PLAU (HUMAN) Activity: U-plasminogen activator, with EC number 3.4.21.73 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 Improving the binding affinity and/or stability of peptide ligands often requires testing of large numbers of variants to identify beneficial mutations. Herein we propose a type of mutation that promises a high success rate. In a bicyclic peptide inhibitor of the cancer-related protease urokinase-type plasminogen activator (uPA), we observed a glycine residue that has a positive varphi dihedral angle when bound to the target. We hypothesized that replacing it with a D-amino acid, which favors positive varphi angles, could enhance the binding affinity and/or proteolytic resistance. Mutation of this specific glycine to D-serine in the bicyclic peptide indeed improved inhibitory activity (1.75-fold) and stability (fourfold). X-ray-structure analysis of the inhibitors in complex with uPA showed that the peptide backbone conformation was conserved. Analysis of known cyclic peptide ligands showed that glycine is one of the most frequent amino acids, and that glycines with positive varphi angles are found in many protein-bound peptides. These results suggest that the glycine-to-D-amino acid mutagenesis strategy could be broadly applied. Improving Binding Affinity and Stability of Peptide Ligands by Substituting Glycines with D-Amino Acids.,Chen S, Gfeller D, Buth SA, Michielin O, Leiman PG, Heinis C Chembiochem. 2013 Jul 4. doi: 10.1002/cbic.201300228. PMID:23828687 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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