2c8x
From Proteopedia
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|PDB= 2c8x |SIZE=350|CAPTION= <scene name='initialview01'>2c8x</scene>, resolution 2.17Å | |PDB= 2c8x |SIZE=350|CAPTION= <scene name='initialview01'>2c8x</scene>, resolution 2.17Å | ||
|SITE= <scene name='pdbsite=AC1:C5m+Binding+Site+For+Chain+B'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:C5m+Binding+Site+For+Chain+B'>AC1</scene> | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=C5M:N-{(2R,3S)-3-[(3-CHLOROBENZYL)AMINO]-2-HYDROXY-4-PHENYLBUTYL}-4-METHOXY-2,3,6-TRIMETHYLBENZENESULFONAMIDE'>C5M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TYS:SULFONATED+TYROSINE'>TYS</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] | + | |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=2c8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c8x OCA], [http://www.ebi.ac.uk/pdbsum/2c8x PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2c8x RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
The screening of fragments is an alternative approach to high-throughput screening for the identification of leads for therapeutic targets. Fragment hits have been discovered using X-ray crystallographic screening of protein crystals of the serine protease enzyme thrombin. The fragment library was designed to avoid any well-precedented, strongly basic functionality. Screening hits included a novel ligand (3), which binds exclusively to the S2-S4 pocket, in addition to smaller fragments which bind to the S1 pocket. The structure of these protein-ligand complexes are presented. A chemistry strategy to link two such fragments together and to synthesize larger drug-sized compounds resulted in the efficient identification of hybrid inhibitors with nanomolar potency (e.g., 7, IC50 = 3.7 nM). These potent ligands occupy the same area of the active site as previously described peptidic inhibitors, while having very different chemical architecture. | The screening of fragments is an alternative approach to high-throughput screening for the identification of leads for therapeutic targets. Fragment hits have been discovered using X-ray crystallographic screening of protein crystals of the serine protease enzyme thrombin. The fragment library was designed to avoid any well-precedented, strongly basic functionality. Screening hits included a novel ligand (3), which binds exclusively to the S2-S4 pocket, in addition to smaller fragments which bind to the S1 pocket. The structure of these protein-ligand complexes are presented. A chemistry strategy to link two such fragments together and to synthesize larger drug-sized compounds resulted in the efficient identification of hybrid inhibitors with nanomolar potency (e.g., 7, IC50 = 3.7 nM). These potent ligands occupy the same area of the active site as previously described peptidic inhibitors, while having very different chemical architecture. | ||
| - | |||
| - | ==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: Murray, C W.]] | [[Category: Murray, C W.]] | ||
[[Category: Seavers, L C.A.]] | [[Category: Seavers, L C.A.]] | ||
| - | [[Category: C5M]] | ||
| - | [[Category: DMS]] | ||
| - | [[Category: NA]] | ||
[[Category: blood coagulation]] | [[Category: blood coagulation]] | ||
[[Category: gamma-carboxyglutamic acid]] | [[Category: gamma-carboxyglutamic acid]] | ||
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[[Category: thrombin]] | [[Category: thrombin]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:18:07 2008'' |
Revision as of 23:18, 30 March 2008
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| , resolution 2.17Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , , | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
THROMBIN INHIBITORS
Overview
The screening of fragments is an alternative approach to high-throughput screening for the identification of leads for therapeutic targets. Fragment hits have been discovered using X-ray crystallographic screening of protein crystals of the serine protease enzyme thrombin. The fragment library was designed to avoid any well-precedented, strongly basic functionality. Screening hits included a novel ligand (3), which binds exclusively to the S2-S4 pocket, in addition to smaller fragments which bind to the S1 pocket. The structure of these protein-ligand complexes are presented. A chemistry strategy to link two such fragments together and to synthesize larger drug-sized compounds resulted in the efficient identification of hybrid inhibitors with nanomolar potency (e.g., 7, IC50 = 3.7 nM). These potent ligands occupy the same area of the active site as previously described peptidic inhibitors, while having very different chemical architecture.
About this Structure
2C8X is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors., Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray CW, Seavers LC, van Montfort RL, J Med Chem. 2006 Feb 23;49(4):1346-55. PMID:16480269
Page seeded by OCA on Mon Mar 31 02:18:07 2008
Categories: Homo sapiens | Protein complex | Thrombin | Abell, C. | Blakemore, W. | Carr, R. | Chessari, G. | Congreve, M. | Howard, N. | Howard, S. | Jhoti, H. | Montfort, R L.M Van. | Murray, C W. | Seavers, L C.A. | Blood coagulation | Gamma-carboxyglutamic acid | Glycoprotein | Hydrolase | Kringle | Protease | Serine protea
