1c4u
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SELECTIVE NON ELECTROPHILIC THROMBIN INHIBITORS WITH CYCLOHEXYL MOIETIES.
OverviewOverview
The crystal structures of five new non-electrophilic beta-strand-templated, thrombin active-site inhibitors have been determined bound to the enzyme., Four co-crystallize with hirugen and inhibitor isomorphously to produce, thrombin-hirugen crystals (monoclinic, space group C2), while one, co-crystallizes in the hexagonal system, space group P6(5). A, 1,4-substituted cyclohexyl moiety is conserved at the P1 position of all, the inhibitors, along with a fused hetero-bicyclic five- and six-membered, ring that occupies the P2 site. Amino, amidino and aminoimidazole groups, are attached to the cyclohexyl ring for recognition at the S1 specificity, site, while benzylsulfonyl and diphenyl groups enhance the binding at the, S3 subsite. The cyclohexyl groups at the P1 positions of three of the, inhibitors appear to be in the energetically favored chair conformation, while the imidazole-substituted cyclohexyl rings are in a boat, conformation. Somewhat unexpectedly, the two cyclohexyl-aminoimidazole, groups bind differently in the specificity site; the unique binding of one, is heretofore unreported. The other inhibitors generally mimic arginyl, binding at S1. This group of inhibitors combines the non-electrophilicity, and selectivity of DAPA-like compounds and the more optimal binding, features of the S1-S3 sites of thrombin for peptidic molecules, which, results in highly potent (binding constants 12 nM-16 pM, one being 1.1, microM) and selective (ranging from 140 to 20 000 times more selective, compared with trypsin) inhibitors of thrombin. The binding modes of these, novel inhibitors are correlated with their binding constants, as is their, selectivity, in order to provide further insight for the design of, therapeutic antithrombotic agents that inhibit thrombin directly at the, active site.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1C4U is a Protein complex structure of sequences from Homo sapiens with NA and IH1 as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
ReferenceReference
Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1., Krishnan R, Mochalkin I, Arni R, Tulinsky A, Acta Crystallogr D Biol Crystallogr. 2000 Mar;56(Pt 3):294-303. PMID:10713516
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