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


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==Structure of HEPATITIS C VIRAL NS3 protease domain complexed with NS4A peptide and ketoamide SCH476776==
The line below this paragraph, containing "STRUCTURE_2obo", creates the "Structure Box" on the page.
<StructureSection load='2obo' size='340' side='right'caption='[[2obo]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2obo]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepacivirus_C Hepacivirus C] and [https://en.wikipedia.org/wiki/Hepatitis_C_virus_subtype_1b Hepatitis C virus subtype 1b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OBO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OBO FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=HUD:TERT-BUTYL+{(2S)-1-[(1R,2S,5S)-2-{[(2S,3R)-4-AMINO-1-CYCLOPROPYL-3-HYDROXY-4-OXOBUTAN-2-YL]CARBAMOYL}-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEX-3-YL]-3,3-DIMETHYL-1-OXOBUTAN-2-YL}CARBAMATE'>HUD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
{{STRUCTURE_2obo|  PDB=2obo  |  SCENE=  }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2obo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2obo OCA], [https://pdbe.org/2obo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2obo RCSB], [https://www.ebi.ac.uk/pdbsum/2obo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2obo ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q9QP06_9HEPC Q9QP06_9HEPC]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


===Discovery of the HCV NS3/4A Protease Inhibitor SCH503034. Key Steps in Structure-Based Optimization===
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<ref>PMID:17444623</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2obo" style="background-color:#fffaf0;"></div>


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==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_17444623}}, adds the Publication Abstract to the page
*[[Virus protease 3D structures|Virus protease 3D structures]]
(as it appears on PubMed at http://www.pubmed.gov), where 17444623 is the PubMed ID number.
== References ==
-->
<references/>
{{ABSTRACT_PUBMED_17444623}}
__TOC__
 
</StructureSection>
==About this Structure==
[[Category: Hepacivirus C]]
2OBO 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=2OBO OCA].
[[Category: Hepatitis C virus subtype 1b]]
 
[[Category: Large Structures]]
==Reference==
[[Category: Arasappan A]]
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: Bennett F]]
 
[[Category: Beyer BM]]
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]
[[Category: Bogen SF]]
 
[[Category: Chen K]]
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]
[[Category: Fischmann T]]
 
[[Category: Girijavallabhan V]]
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]
[[Category: Guo Z]]
 
[[Category: Hong Z]]
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]
[[Category: Ingram R]]
 
[[Category: Jao E]]
Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations., Yi M, Tong X, Skelton A, Chase R, Chen T, Prongay A, Bogen SL, Saksena AK, Njoroge FG, Veselenak RL, Pyles RB, Bourne N, Malcolm BA, Lemon SM, J Biol Chem. 2006 Mar 24;281(12):8205-15. Epub 2005 Dec 13. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16352601 16352601]
[[Category: Liu Y]]
[[Category: Hepatitis c virus]]
[[Category: Love RG]]
[[Category: Protein complex]]
[[Category: Madison V]]
[[Category: Arasappan, A.]]
[[Category: Malcolm B]]
[[Category: Bennett, F.]]
[[Category: Myers Jr J]]
[[Category: Beyer, B M.]]
[[Category: Njoroge FG]]
[[Category: Bogen, S F.]]
[[Category: Pichardo J]]
[[Category: Chen, K.]]
[[Category: Prongay AJ]]
[[Category: Fischmann, T.]]
[[Category: Prosise WW]]
[[Category: Girijavallabhan, V.]]
[[Category: Ramanathan L]]
[[Category: Guo, Z.]]
[[Category: Saksena AK]]
[[Category: Hong, Z.]]
[[Category: Senior M]]
[[Category: Ingram, R.]]
[[Category: Strickland C]]
[[Category: Jao, E.]]
[[Category: Taremi SS]]
[[Category: Liu, Y.]]
[[Category: Venkatraman S]]
[[Category: Love, R G.]]
[[Category: Weber PC]]
[[Category: Madison, V.]]
[[Category: Yang R]]
[[Category: Malcolm, B.]]
[[Category: Yao N]]
[[Category: Myers, Jr., J.]]
[[Category: Yarosh-Tomaine T]]
[[Category: Njoroge, F G.]]
[[Category: Zhang R]]
[[Category: Pichardo, J.]]
[[Category: Prongay, A J.]]
[[Category: Prosise, W W.]]
[[Category: Ramanathan, L.]]
[[Category: Saksena, A K.]]
[[Category: Senior, M.]]
[[Category: Strickland, C.]]
[[Category: Taremi, S S.]]
[[Category: Venkatraman, S.]]
[[Category: Weber, P C.]]
[[Category: Yang, R.]]
[[Category: Yao, N.]]
[[Category: Yarosh-Tomaine, T.]]
[[Category: Zhang, R.]]
[[Category: Hcv]]
[[Category: Hepatitis c virus]]
[[Category: Ketoamide inhibitor]]
[[Category: Ns3 protease]]
[[Category: Viral protein]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 04:44:21 2008''

Latest revision as of 13:34, 30 August 2023

Structure of HEPATITIS C VIRAL NS3 protease domain complexed with NS4A peptide and ketoamide SCH476776Structure of HEPATITIS C VIRAL NS3 protease domain complexed with NS4A peptide and ketoamide SCH476776

Structural highlights

2obo is a 4 chain structure with sequence from Hepacivirus C and Hepatitis C virus subtype 1b. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.6Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q9QP06_9HEPC

Publication Abstract from PubMed

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.

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[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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. 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. J Med Chem. 2007 May 17;50(10):2310-8. Epub 2007 Apr 20. PMID:17444623 doi:10.1021/jm060173k

2obo, resolution 2.60Å

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