4mnw

Crystal structure of urokinase-type plasminogen activator (uPA) complexed with bicyclic peptide UK749

spinqualitylabelsall models 4mnw, resolution 1.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4mnw is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.49Å Ligands: ACT, GOL, NH2, SO4, ZBR 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 Bicyclic peptides generated through directed evolution by using phage display offer an attractive ligand format for the development of therapeutics. Being nearly 100-fold smaller than antibodies, they promise advantages such as access to chemical synthesis, efficient diffusion into tissues, and needle-free application. However, unlike antibodies, they do not have a folded structure in solution and thus bind less well. We developed bicyclic peptides with hydrophilic chemical structures at their center to promote noncovalent intramolecular interactions, thereby stabilizing the peptide conformation. The sequences of the peptides isolated by phage display from large combinatorial libraries were strongly influenced by the type of small molecule used in the screen, thus suggesting that the peptides fold around the small molecules. X-ray structure analysis revealed that the small molecules indeed formed hydrogen bonds with the peptides. These noncovalent interactions stabilize the peptide-protein complexes and contribute to the high binding affinity. Peptide ligands stabilized by small molecules.,Chen S, Bertoldo D, Angelini A, Pojer F, Heinis C Angew Chem Int Ed Engl. 2014 Feb 3;53(6):1602-6. doi: 10.1002/anie.201309459., Epub 2014 Jan 22. PMID:24453110 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Plasminogen activator Urokinase 3D Structures

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