4gly
From Proteopedia
Human urokinase-type plasminogen activator uPA in complex with the two-disulfide bridge peptide UK504
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 PubMedBicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format XmCXnCXoCXp are oxidized to connect two pairs of cysteines (C). This allows the generation of 3 x (m + n + o + p) different peptide topologies because the fourth cysteine can appear in any of the (m + n + o + p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities. Bicyclic Peptide Ligands Pulled out of Cysteine-Rich Peptide Libraries.,Chen S, Rentero Rebollo I, Buth SA, Morales-Sanfrutos J, Touati J, Leiman PG, Heinis C J Am Chem Soc. 2013 May 1;135(17):6562-9. doi: 10.1021/ja400461h. Epub 2013 Apr, 17. PMID:23560397[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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