2oc0: Difference between revisions
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'''Structure of NS3 complexed with a ketoamide inhibitor SCh491762''' | {{Structure | ||
|PDB= 2oc0 |SIZE=350|CAPTION= <scene name='initialview01'>2oc0</scene>, resolution 2.3Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene> and <scene name='pdbligand=HU1:TERT-BUTYL {(1S)-2-[(1R,2S,5S)-2-({[(1S)-3-AMINO-1-(CYCLOBUTYLMETHYL)-2,3-DIOXOPROPYL]AMINO}CARBONYL)-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEX-3-YL]-1-CYCLOHEXYL-2-OXOETHYL}CARBAMATE'>HU1</scene> | |||
|ACTIVITY= | |||
|GENE= NS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11103 Hepatitis C virus]) | |||
}} | |||
'''Structure of NS3 complexed with a ketoamide inhibitor SCh491762''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
2OC0 is a [ | 2OC0 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OC0 OCA]. | ||
==Reference== | ==Reference== | ||
Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl] - 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization., Prongay AJ, Guo Z, Yao N, Pichardo J, Fischmann T, Strickland C, Myers J Jr, Weber PC, Beyer BM, Ingram R, Hong Z, Prosise WW, Ramanathan L, Taremi SS, Yarosh-Tomaine T, Zhang R, Senior M, Yang RS, Malcolm B, Arasappan A, Bennett F, Bogen SL, Chen K, Jao E, Liu YT, Lovey RG, Saksena AK, Venkatraman S, Girijavallabhan V, Njoroge FG, Madison V, J Med Chem. 2007 May 17;50(10):2310-8. Epub 2007 Apr 20. PMID:[http:// | Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl] - 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization., Prongay AJ, Guo Z, Yao N, Pichardo J, Fischmann T, Strickland C, Myers J Jr, Weber PC, Beyer BM, Ingram R, Hong Z, Prosise WW, Ramanathan L, Taremi SS, Yarosh-Tomaine T, Zhang R, Senior M, Yang RS, Malcolm B, Arasappan A, Bennett F, Bogen SL, Chen K, Jao E, Liu YT, Lovey RG, Saksena AK, Venkatraman S, Girijavallabhan V, Njoroge FG, Madison V, J Med Chem. 2007 May 17;50(10):2310-8. Epub 2007 Apr 20. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17444623 17444623] | ||
[[Category: Hepatitis c virus]] | [[Category: Hepatitis c virus]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: viral protein]] | [[Category: viral protein]] | ||
''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 17:57:50 2008'' | ||
Revision as of 18:57, 20 March 2008
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| , resolution 2.3Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , and | ||||||
| Gene: | NS3 (Hepatitis C virus) | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure of NS3 complexed with a ketoamide inhibitor SCh491762
OverviewOverview
The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.
About this StructureAbout this Structure
2OC0 is a Protein complex structure of sequences from Hepatitis c virus. Full crystallographic information is available from OCA.
ReferenceReference
Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl] - 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization., Prongay AJ, Guo Z, Yao N, Pichardo J, Fischmann T, Strickland C, Myers J Jr, Weber PC, Beyer BM, Ingram R, Hong Z, Prosise WW, Ramanathan L, Taremi SS, Yarosh-Tomaine T, Zhang R, Senior M, Yang RS, Malcolm B, Arasappan A, Bennett F, Bogen SL, Chen K, Jao E, Liu YT, Lovey RG, Saksena AK, Venkatraman S, Girijavallabhan V, Njoroge FG, Madison V, J Med Chem. 2007 May 17;50(10):2310-8. Epub 2007 Apr 20. PMID:17444623
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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
- Hepatitis c virus
- Protein complex
- Arasappan, A.
- Bennett, F.
- Beyer, B M.
- Bogen, S F.
- Chen, K.
- Fischmann, T.
- Girijavallabhan, V.
- Guo, Z.
- Hong, Z.
- Ingram, R.
- Jao, E.
- Liu, Y.
- Love, R G.
- Madison, V.
- Malcolm, B.
- Myers, Jr., J.
- Njoroge, F G.
- Pichardo, J.
- Prongay, A J.
- Prosise, W W.
- Ramanathan, L.
- Saksena, A K.
- Senior, M.
- Strickland, C.
- Taremi, S S.
- Venkatraman, S.
- Weber, P C.
- Yang, R.
- Yao, N.
- Yarosh-Tomaine, T.
- Zhang, R.
- BME
- HU1
- ZN
- Hcv
- Ketoamide inhibitor
- Ns3 protease domain
- Viral protein