1d3q

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spinqualitylabelsall models 1d3q, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 2

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]

About this Structure

1D3Q is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with NAG, NA and BT2 as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.

Reference

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]]

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