1lmw
From Proteopedia
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LMW U-PA STRUCTURE COMPLEXED WITH EGRCMK (GLU-GLY-ARG CHLOROMETHYL KETONE)
Contents |
Overview
BACKGROUND: Urokinase-type plasminogen activator (u-PA) promotes, fibrinolysis by catalyzing the conversion of plasminogen to the active, protease plasmin via the cleavage of a peptide bond. When localized to the, external cell surface it contributes to tissue remodelling and cellular, migration; inhibition of its activity impedes the spread of cancer. u-PA, has three domains: an N-terminal receptor-binding growth factor domain, a, central kringle domain and a C-terminal catalytic protease domain. The, biological roles of the fibrinolytic enzymes render them therapeutic, targets, however, until now no structure of the protease domain has been, available. Solution of the structure of the u-PA serine protease was, undertaken to provide such data. RESULTS: The crystal structure of the, catalytic domain of recombinant, non-glycosylated human u-PA, complexed, with the inhibitor Glu-Gly-Arg chloromethyl ketone (EGRcmk), has been, determined at a nominal resolution of 2.5 A and refined to a, crystallographic R-factor of 22.4% on all data (20.4% on data > 3 sigma)., The enzyme has the expected topology of a trypsin-like serine protease., CONCLUSIONS: The enzyme has an S1 specificity pocket similar to that of, trypsin, a restricted, less accessible, hydrophobic S2 pocket and a, solvent-accessible S3 pocket which is capable of accommodating a wide, range of residues. The EGRcmk inhibitor binds covalently at the active, site to form a tetrahedral hemiketal structure. Although the overall, structure is similar to that of homologous serine proteases, at six, positions insertions of extra residues in loop regions create unique, surface areas. One of these loop regions is highly mobile despite being, anchored by the disulphide bridge which is characteristic of a small, subset of serine proteases namely tissuetype plasminogen activator, Factor, XII and Complement Factor I.
Disease
Known disease associated with this structure: Alzheimer disease, late-onset, susceptibility to OMIM:[191840]
About this Structure
1LMW is a Single protein structure of sequence from Homo sapiens. Active as U-plasminogen activator, with EC number 3.4.21.73 Full crystallographic information is available from OCA.
Reference
The crystal structure of the catalytic domain of human urokinase-type plasminogen activator., Spraggon G, Phillips C, Nowak UK, Ponting CP, Saunders D, Dobson CM, Stuart DI, Jones EY, Structure. 1995 Jul 15;3(7):681-91. PMID:8591045
Page seeded by OCA on Mon Nov 12 18:02:36 2007
