2oc8: Difference between revisions

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[[Image:2oc8.jpg|left|200px]]
{{Seed}}
[[Image:2oc8.png|left|200px]]


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{{STRUCTURE_2oc8|  PDB=2oc8  |  SCENE=  }}  
{{STRUCTURE_2oc8|  PDB=2oc8  |  SCENE=  }}  


'''Structure of Hepatitis C Viral NS3 protease domain complexed with NS4A peptide and ketoamide SCH503034'''
===Structure of Hepatitis C Viral NS3 protease domain complexed with NS4A peptide and ketoamide SCH503034===




==Overview==
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An estimated 1% of the global human population is infected by hepatitis C viruses (HCVs), and there are no broadly effective treatments for the debilitating progression of chronic hepatitis C. A serine protease located within the HCV NS3 protein processes the viral polyprotein at four specific sites and is considered essential for replication. Thus, it emerges as an attractive target for drug design. We report here the 2.5 angstrom resolution X-ray crystal structure of the NS3 protease domain complexed with a synthetic NS4A activator peptide. The protease has a chymotrypsin-like fold and features a tetrahedrally coordinated metal ion distal to the active site. The NS4A peptide intercalates within a beta sheet of the enzyme core.
The line below this paragraph, {{ABSTRACT_PUBMED_17444623}}, adds the Publication Abstract to the page
(as it appears on PubMed at http://www.pubmed.gov), where 17444623 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17444623}}


==About this Structure==
==About this Structure==
2OC8 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=2OC8 OCA].  
2OC8 is a 4 chains 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=2OC8 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://www.ncbi.nlm.nih.gov/pubmed/17444623 17444623]
Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide., Kim JL, Morgenstern KA, Lin C, Fox T, Dwyer MD, Landro JA, Chambers SP, Markland W, Lepre CA, O'Malley ET, Harbeson SL, Rice CM, Murcko MA, Caron PR, Thomson JA, Cell. 1996 Oct 18;87(2):343-55. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/8861917 8861917]
Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide., Kim JL, Morgenstern KA, Lin C, Fox T, Dwyer MD, Landro JA, Chambers SP, Markland W, Lepre CA, O'Malley ET, Harbeson SL, Rice CM, Murcko MA, Caron PR, Thomson JA, Cell. 1996 Oct 18;87(2):343-55. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/8861917 8861917]
Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency., Arasappan A, Njoroge FG, Chan TY, Bennett F, Bogen SL, Chen K, Gu H, Hong L, Jao E, Liu YT, Lovey RG, Parekh T, Pike RE, Pinto P, Santhanam B, Venkatraman S, Vaccaro H, Wang H, Yang X, Zhu Z, Mckittrick B, Saksena AK, Girijavallabhan V, Pichardo J, Butkiewicz N, Ingram R, Malcolm B, Prongay A, Yao N, Marten B, Madison V, Kemp S, Levy O, Lim-Wilby M, Tamura S, Ganguly AK, Bioorg Med Chem Lett. 2005 Oct 1;15(19):4180-4. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16087332 16087332]
Synthesis and biological activity of macrocyclic inhibitors of hepatitis C virus (HCV) NS3 protease., Chen KX, Njoroge FG, Prongay A, Pichardo J, Madison V, Girijavallabhan V, Bioorg Med Chem Lett. 2005 Oct 15;15(20):4475-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16112859 16112859]
Hepatitis C virus NS3-4A serine protease inhibitors: use of a P2-P1 cyclopropyl alanine combination for improved potency., Bogen S, Saksena AK, Arasappan A, Gu H, Njoroge FG, Girijavallabhan V, Pichardo J, Butkiewicz N, Prongay A, Madison V, Bioorg Med Chem Lett. 2005 Oct 15;15(20):4515-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16112862 16112862]
Depeptidization efforts on P3-P2' alpha-ketoamide inhibitors of HCV NS3-4A serine protease: effect on HCV replicon activity., Bogen SL, Ruan S, Liu R, Agrawal S, Pichardo J, Prongay A, Baroudy B, Saksena AK, Girijavallabhan V, Njoroge FG, Bioorg Med Chem Lett. 2006 Mar 15;16(6):1621-7. Epub 2006 Jan 4. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16387495 16387495]
[[Category: Hepatitis c virus]]
[[Category: Hepatitis c virus]]
[[Category: Protein complex]]
[[Category: Arasappan, A.]]
[[Category: Arasappan, A.]]
[[Category: Bennett, F.]]
[[Category: Bennett, F.]]
[[Category: Beyer, B M.]]
[[Category: Beyer, B M.]]
[[Category: Bogen, S F.]]
[[Category: Bogen, S L.]]
[[Category: Chen, K.]]
[[Category: Chen, K.]]
[[Category: Fischmann, T.]]
[[Category: Fischmann, T.]]
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[[Category: Ingram, R.]]
[[Category: Ingram, R.]]
[[Category: Jao, E.]]
[[Category: Jao, E.]]
[[Category: Liu, Y.]]
[[Category: Liu, Y T.]]
[[Category: Love, R G.]]
[[Category: Lovey, R G.]]
[[Category: Madison, V.]]
[[Category: Madison, V.]]
[[Category: Malcolm, B.]]
[[Category: Malcolm, B.]]
[[Category: Myers, Jr., J.]]
[[Category: Myers, J.]]
[[Category: Njoroge, F G.]]
[[Category: Njoroge, F G.]]
[[Category: Pichardo, J.]]
[[Category: Pichardo, J.]]
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[[Category: Venkatraman, S.]]
[[Category: Venkatraman, S.]]
[[Category: Weber, P C.]]
[[Category: Weber, P C.]]
[[Category: Yang, R.]]
[[Category: Yang, R S.]]
[[Category: Yao, N.]]
[[Category: Yao, N.]]
[[Category: Yarosh-Tomaine, T.]]
[[Category: Yarosh-Tomaine, T.]]
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[[Category: Ns3 protease domain]]
[[Category: Ns3 protease domain]]
[[Category: Viral protein]]
[[Category: Viral protein]]
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