1d3d
CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZOTHIOPHENE INHIBITOR 4
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OverviewOverview
The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and, refined at up to 2.0 A resolution using X-ray crystallography. These, compounds belong to a structurally novel family of inhibitors based on a, 2,3-disubstituted benzo[b]thiophene structure. Compared to traditional, active-site directed inhibitors, the X-ray crystal structures of these, complexes reveal a novel binding mode. Unexpectedly, the lipophilic, benzo[b]thiophene nucleus of the inhibitor appears to bind in the S1, specificity pocket. At the same time, the basic amine of the C-3 side, chain of the inhibitor interacts with the mostly hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine side chain at C-2, was found to point away from the active site, occupying a location between, the S1 and S1' sites. Together, the aromatic rings of the C-2 and C-3 side, chains sandwich the indole ring of Trp60D contained in the thrombin S2, insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin, residue numbering used in this study is equivalent to that reported for, chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New, York: Academic Press. pp 323-373).] In contrast to the binding mode of, more classical thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of benzo[b]thiophene derivatives does not engage in, hydrogen bond formation with Gly216 of the thrombin active site. A, detailed analysis of the three-dimensional structures not only provides a, clearer understanding of the interaction of these agents with thrombin, but forms a foundation for rational structure-based drug design. The use, of the data from this study has led to the design of derivatives that are, up to 2,900-fold more potent than the screening hit 1.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1D3D is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with , and as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
ReferenceReference
The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors., Chirgadze NY, Sall DJ, Briggs SL, Clawson DK, Zhang M, Smith GF, Schevitz RW, Protein Sci. 2000 Jan;9(1):29-36. PMID:10739244 [[Category: thrombin; benzo[b]thiophene; blood clotting]]
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