2c93: Difference between revisions
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|PDB= 2c93 |SIZE=350|CAPTION= <scene name='initialview01'>2c93</scene>, resolution 2.20Å | |PDB= 2c93 |SIZE=350|CAPTION= <scene name='initialview01'>2c93</scene>, resolution 2.20Å | ||
|SITE= <scene name='pdbsite=AC1:C4m+Binding+Site+For+Chain+B'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:C4m+Binding+Site+For+Chain+B'>AC1</scene> | ||
|LIGAND= <scene name='pdbligand= | |LIGAND= <scene name='pdbligand=C4M:N-[(2R,3S)-3-AMINO-2-HYDROXY-4-PHENYLBUTYL]-4-METHOXY-2,3,6-TRIMETHYLBENZENESULFONAMIDE'>C4M</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=2c93 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c93 OCA], [http://www.ebi.ac.uk/pdbsum/2c93 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2c93 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. | ||
==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: 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 02:18:11 2008'' | ||
Revision as of 02:18, 31 March 2008
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| , resolution 2.20Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , , | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
THROMBIN INHIBITORS
OverviewOverview
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 StructureAbout this Structure
2C93 is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Hirudo medicinalis
- 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 protease