1d3q: Difference between revisions
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==Overview== | ==Overview== | ||
The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and | 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== | ==Disease== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Thrombin]] | [[Category: Thrombin]] | ||
[[Category: Chirgadze, N | [[Category: Chirgadze, N Y.]] | ||
[[Category: BT2]] | [[Category: BT2]] | ||
[[Category: NA]] | [[Category: NA]] | ||
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[[Category: thrombin; benzo[b]thiophene]] | [[Category: thrombin; benzo[b]thiophene]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:12:45 2008'' | ||
Revision as of 10:12, 21 February 2008
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CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 2
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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