1bjv

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spinqualitylabelsall models 1bjv, resolution 1.8Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

BETA-TRYPSIN COMPLEXED WITH APPU

Overview

Novel aryl derivatives of benzamidine were synthesized and tested for, their inhibitory potency against bovine trypsin, rat skin tryptase, human, recombinant granzyme A, human thrombin, and human plasma kallikrein. All, compounds show competitive inhibition against these proteases with Ki, values in the micromolar range. X-ray structures were determined to 1.8 A, resolution for trypsin complexed with two of the para-substituted, benzamidine derivatives, 1-(4-amidinophenyl)-3-(4-chlorophenyl)urea (ACPU), and 1-(4-amidinophenyl)-3-(4-phenoxyphenyl)urea (APPU). Although the, inhibitors do not engage in direct and specific interactions outside the, S1 pocket, they do form intimate indirect contacts with the active site of, trypsin. The inhibitors are linked to the enzyme by a sulfate ion that, forms an intricate network of three-centered hydrogen bonds. Comparison of, these structures with other serine protease structures with noncovalently, bound oxyanions reveals a pair of highly conserved oxyanion-binding sites, in the active site. The positions of noncovalently bound oxyanions, such, as the oxygen atoms of sulfate, are distinct from the positions of, covalent oxyanions of tetrahedral intermediates. Noncovalent oxyanion, positions are outside the "oxyanion hole." Kinetics data suggest that, protonation stabilizes the ternary inhibitor/oxyanion/protease complex. In, sum, both cations and anions can mediate Ki. Cation mediation of potency, of competitive inhibitors of serine proteases was previously reported by, Stroud and co-workers [Katz, B. A., Clark, J. M., Finer-Moore, J. S., Jenkins, T. E., Johnson, C. R., Ross, M. J., Luong, C., Moore, W. R., and, Stroud, R. M. (1998) Nature 391, 608-612].

About this Structure

1BJV is a Single protein structure of sequence from Bos taurus with CA, SO4, DMS and GP8 as ligands. Active as Trypsin, with EC number 3.4.21.4 Full crystallographic information is available from OCA.

Reference

Oxyanion-mediated inhibition of serine proteases., Presnell SR, Patil GS, Mura C, Jude KM, Conley JM, Bertrand JA, Kam CM, Powers JC, Williams LD, Biochemistry. 1998 Dec 1;37(48):17068-81. PMID:9836602

Page seeded by OCA on Tue Nov 20 11:42:31 2007