4zhl
From Proteopedia
The crystal structure of mupain-1-IG in complex with murinised human uPA at pH7.4
Structural highlights
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.[1] Function[UROK_HUMAN] Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. Publication Abstract from PubMedWe have developed a new concept for designing peptidic protein modulators, by recombinantly fusing the peptidic modulator, with randomized residues, directly to the target protein via a linker and screening for internal modulation of the activity of the protein. We tested the feasibility of the concept by fusing a 10-residue-long, disulfide-bond-constrained inhibitory peptide, randomized in selected positions, to the catalytic domain of the serine protease murine urokinase-type plasminogen activator. High-affinity inhibitory peptide variants were identified as those that conferred to the fusion protease the lowest activity for substrate hydrolysis. The usefulness of the strategy was demonstrated by the selection of peptidic inhibitors of murine urokinase-type plasminogen activator with a low nanomolar affinity. The high affinity could not have been predicted by rational considerations, as the high affinity was associated with a loss of polar interactions and an increased binding entropy. Selection of High-Affinity Peptidic Serine Protease Inhibitors with Increased Binding Entropy from a Back-Flip Library of Peptide-Protease Fusions.,Sorensen HP, Xu P, Jiang L, Kromann-Hansen T, Jensen KJ, Huang M, Andreasen PA J Mol Biol. 2015 Sep 25;427(19):3110-22. doi: 10.1016/j.jmb.2015.08.005. Epub, 2015 Aug 14. PMID:26281711[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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