1hbt | pdb_00001hbt
HUMAN ALPHA-THROMBIN COMPLEXED WITH A PEPTIDYL PYRIDINIUM METHYL KETONE CONTAINING BIVALENT INHIBITOR
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Overview
The crystal structure of a complex between a bivalent peptidyl pyridinium, methyl ketone inhibitor and human alpha-thrombin has been solved and, refined at 2.0 A to an R factor of 0.18. The inhibitor, (D)cyclohexylalanine-Pro-Arg-(CH2N+C5H4CH2CO)-(Gly)4-Asp-, Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-cyclo-hexylalanine-(D)Glu (coded P596), which forms a reversible covalent complex with thrombin, is highly potent, with a Ki = 4.6 +/- 1.0 x 10(-14) M, lower than that of recombinant, hirudin. The N-terminal, active-site-directed portion of the inhibitor is, linked to the fibrinogen recognition exosite binding portion by a, tetraglycine segment. The strong electron-withdrawing effect provided by, the permanent positive charge on the pyridinium nitrogen makes the arginyl, carbonyl carbon more susceptible to nucleophilic attack. In the crystal, a, covalent P596-thrombin complex is observed. The electron density, surrounding the active site portion and the pyridinium of the inhibitor is, very well defined, clearly showing the existence of a covalent bond, between the Ser195 O gamma and the now tetrahedral carbon of the, inhibitor. The decreased binding ability of thrombin inhibitors containing, N-terminal acetylation is discussed as is the effect of replacing the P3, (D)phenylalanine with (D)cyclohexylalanine. The electron density, surrounding the remainder of the inhibitor is generally well defined, the, exceptions being the C-terminal (D)Glu, the highly flexible tetraglycine, linker, and some of the solvent-directed side chains.(ABSTRACT TRUNCATED, AT 250 WORDS)
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1HBT is a Protein complex structure of sequences from Homo sapiens with CHX as ligand. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
Reference
Crystal structure of a peptidyl pyridinium methyl ketone inhibitor with thrombin., Rehse PH, Steinmetzer T, Li Y, Konishi Y, Cygler M, Biochemistry. 1995 Sep 12;34(36):11537-44. PMID:7547884
Page seeded by OCA on Mon Nov 12 17:15:22 2007
