1d3q: Difference between revisions
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'''CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 2''' | {{Structure | ||
|PDB= 1d3q |SIZE=350|CAPTION= <scene name='initialview01'>1d3q</scene>, resolution 2.90Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene> and <scene name='pdbligand=BT2:3-[4-(2-PYRROLIDIN-1-YL-ETHOXY)-BENZYL]-2-4-(2-PYRROLIDIN-1-YL-ETHOXY)-PHENYL] -BENZO[B]THIOPHENE'>BT2</scene> | |||
|ACTIVITY= [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] | |||
|GENE= | |||
}} | |||
'''CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 2''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1D3Q is a [ | 1D3Q is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D3Q OCA]. | ||
==Reference== | ==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:[http:// | 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:[http://www.ncbi.nlm.nih.gov/pubmed/10739244 10739244] | ||
[[Category: Hirudo medicinalis]] | [[Category: Hirudo medicinalis]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
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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 Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:32:30 2008'' | ||
Revision as of 11:32, 20 March 2008
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| , resolution 2.90Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , and | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF HUMAN ALPHA THROMBIN IN COMPLEX WITH BENZO[B]THIOPHENE INHIBITOR 2
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
1D3Q is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens. 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]]
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