1thr
From Proteopedia
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|SITE= | |SITE= | ||
|LIGAND= | |LIGAND= | ||
| - | |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] | + | |ACTIVITY= <span class='plainlinks'>[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] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1thr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1thr OCA], [http://www.ebi.ac.uk/pdbsum/1thr PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1thr RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
The structures of two hirudin-based fibrinogen recognition exosite peptide inhibitors with significantly different sequences complexed with alpha-thrombin at a site distinct from the active site (exosite) have been determined crystallographically at 2.2 and 2.3 A resolution. One is a designed synthetic peptide with some nonconventional amino acid residues (MDL-28050), and the other is a natural COOH-terminal peptide isolated from the leech Hirudinaria manillensis (hirullin P18). The structures have been refined by restrained least squares methods to R values of 0.161 and 0.155, respectively. The first stretch of each peptide, corresponding to hirudin 55-59, associates with thrombin similar to hirudin and hirugen (hirudin 53-64). Although the remaining residues of the inhibitors interact with and bind to thrombin, the binding is accomplished. through a rigid body conformational adjustment of the peptide with respect to the conformation displayed by hirudin and hirugen (40 degrees rotation about the Ile59, CA-C bond). This causes the side groups of cyclohexylalanine 64' of MDL-28050 and Ile60, of hirullin to point in the opposite direction of the all important Tyr63, ring of hirudin and hirugen but permits the residues to penetrate and interact with the 3(10) turn hydrophobic binding pocket of thrombin. Thus, the hydrophobic interaction is accomplished in a different way by virtue of the substrate conformational readjustment. The results show that the first stretch of peptide makes concerted and efficient binding interactions with thrombin, and the peptide positions of the inhibitors are fairly specific and homologous so that the stretch appears to be related to specific recognition associated with the exosite. The relative flexibility of structure and sequence of the second stretch is a display of tolerance of imprecision by thrombin in its COOH-terminal hydrophobic association with hirudin-based inhibitors. | The structures of two hirudin-based fibrinogen recognition exosite peptide inhibitors with significantly different sequences complexed with alpha-thrombin at a site distinct from the active site (exosite) have been determined crystallographically at 2.2 and 2.3 A resolution. One is a designed synthetic peptide with some nonconventional amino acid residues (MDL-28050), and the other is a natural COOH-terminal peptide isolated from the leech Hirudinaria manillensis (hirullin P18). The structures have been refined by restrained least squares methods to R values of 0.161 and 0.155, respectively. The first stretch of each peptide, corresponding to hirudin 55-59, associates with thrombin similar to hirudin and hirugen (hirudin 53-64). Although the remaining residues of the inhibitors interact with and bind to thrombin, the binding is accomplished. through a rigid body conformational adjustment of the peptide with respect to the conformation displayed by hirudin and hirugen (40 degrees rotation about the Ile59, CA-C bond). This causes the side groups of cyclohexylalanine 64' of MDL-28050 and Ile60, of hirullin to point in the opposite direction of the all important Tyr63, ring of hirudin and hirugen but permits the residues to penetrate and interact with the 3(10) turn hydrophobic binding pocket of thrombin. Thus, the hydrophobic interaction is accomplished in a different way by virtue of the substrate conformational readjustment. The results show that the first stretch of peptide makes concerted and efficient binding interactions with thrombin, and the peptide positions of the inhibitors are fairly specific and homologous so that the stretch appears to be related to specific recognition associated with the exosite. The relative flexibility of structure and sequence of the second stretch is a display of tolerance of imprecision by thrombin in its COOH-terminal hydrophobic association with hirudin-based inhibitors. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: hydrolase(serine proteinase)]] | [[Category: hydrolase(serine proteinase)]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:56:12 2008'' |
Revision as of 20:56, 30 March 2008
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| , resolution 2.3Å | |||||||
|---|---|---|---|---|---|---|---|
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
STRUCTURES OF THROMBIN COMPLEXES WITH A DESIGNED AND A NATURAL EXOSITE INHIBITOR
Overview
The structures of two hirudin-based fibrinogen recognition exosite peptide inhibitors with significantly different sequences complexed with alpha-thrombin at a site distinct from the active site (exosite) have been determined crystallographically at 2.2 and 2.3 A resolution. One is a designed synthetic peptide with some nonconventional amino acid residues (MDL-28050), and the other is a natural COOH-terminal peptide isolated from the leech Hirudinaria manillensis (hirullin P18). The structures have been refined by restrained least squares methods to R values of 0.161 and 0.155, respectively. The first stretch of each peptide, corresponding to hirudin 55-59, associates with thrombin similar to hirudin and hirugen (hirudin 53-64). Although the remaining residues of the inhibitors interact with and bind to thrombin, the binding is accomplished. through a rigid body conformational adjustment of the peptide with respect to the conformation displayed by hirudin and hirugen (40 degrees rotation about the Ile59, CA-C bond). This causes the side groups of cyclohexylalanine 64' of MDL-28050 and Ile60, of hirullin to point in the opposite direction of the all important Tyr63, ring of hirudin and hirugen but permits the residues to penetrate and interact with the 3(10) turn hydrophobic binding pocket of thrombin. Thus, the hydrophobic interaction is accomplished in a different way by virtue of the substrate conformational readjustment. The results show that the first stretch of peptide makes concerted and efficient binding interactions with thrombin, and the peptide positions of the inhibitors are fairly specific and homologous so that the stretch appears to be related to specific recognition associated with the exosite. The relative flexibility of structure and sequence of the second stretch is a display of tolerance of imprecision by thrombin in its COOH-terminal hydrophobic association with hirudin-based inhibitors.
About this Structure
1THR is a Protein complex structure of sequences from Hirudinaria manillensis and Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structures of thrombin complexes with a designed and a natural exosite peptide inhibitor., Qiu X, Yin M, Padmanabhan KP, Krstenansky JL, Tulinsky A, J Biol Chem. 1993 Sep 25;268(27):20318-26. PMID:8376390
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