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==Structure of HEPATITIS C VIRAL NS3 protease domain complexed with NS4A peptide and ketoamide SCH476776== | |||
<StructureSection load='2obo' size='340' side='right'caption='[[2obo]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
| | == Structural highlights == | ||
<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> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> | |||
<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> | |||
<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. | 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<ref>PMID:17444623</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2obo" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Virus protease 3D structures|Virus protease 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Hepacivirus C]] | |||
[[Category: Hepatitis C virus subtype 1b]] | |||
[[Category: Large Structures]] | |||
[[Category: Arasappan A]] | |||
[[Category: Bennett F]] | |||
[[Category: Beyer BM]] | |||
[[Category: Bogen SF]] | |||
[[Category: Chen K]] | |||
[[Category: Fischmann T]] | |||
[[Category: Girijavallabhan V]] | |||
[[Category: Guo Z]] | |||
[[Category: Hong Z]] | |||
[[Category: Ingram R]] | |||
[[Category: Jao E]] | |||
[[Category: Liu Y]] | |||
[[Category: Love RG]] | |||
[[Category: Madison V]] | |||
[[Category: Malcolm B]] | |||
[[Category: Myers Jr J]] | |||
[[Category: Njoroge FG]] | |||
[[Category: Pichardo J]] | |||
[[Category: Prongay AJ]] | |||
[[Category: Prosise WW]] | |||
[[Category: Ramanathan L]] | |||
[[Category: Saksena AK]] | |||
[[Category: Senior M]] | |||
[[Category: Strickland C]] | |||
[[Category: Taremi SS]] | |||
[[Category: Venkatraman S]] | |||
[[Category: Weber PC]] | |||
[[Category: Yang R]] | |||
[[Category: Yao N]] | |||
[[Category: Yarosh-Tomaine T]] | |||
[[Category: Zhang R]] | |||