View source for 2d3u


==X-ray crystal structure of hepatitis C virus RNA dependent RNA polymerase in complex with non-nucleoside analogue inhibitor==
<StructureSection load='2d3u' size='340' side='right'caption='[[2d3u]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2d3u]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepacivirus_C Hepacivirus C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2D3U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2D3U 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CCT:5-(4-CYANOPHENYL)-3-{[(2-METHYLPHENYL)SULFONYL]AMINO}THIOPHENE-2-CARBOXYLIC+ACID'>CCT</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=2d3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2d3u OCA], [https://pdbe.org/2d3u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2d3u RCSB], [https://www.ebi.ac.uk/pdbsum/2d3u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2d3u ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q99AU2_9HEPC Q99AU2_9HEPC] 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d3/2d3u_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2d3u ConSurf].
<div style="clear:both"></div>
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== Publication Abstract from PubMed ==
The RNA-dependent RNA polymerase (NS5B) from hepatitis C virus (HCV) is a key enzyme in HCV replication. NS5B is a major target for the development of antiviral compounds directed against HCV. Here we present the structures of three thiophene-based non-nucleoside inhibitors (NNIs) bound non-covalently to NS5B. Each of the inhibitors binds to NS5B non-competitively to a common binding site in the "thumb" domain that is approximately 35 Angstroms from the polymerase active site located in the "palm" domain. The three compounds exhibit IC(50) values in the range of 270 nM to 307 nM and have common binding features that result in relatively large conformational changes of residues that interact directly with the inhibitors as well as for other residues adjacent to the binding site. Detailed comparisons of the unbound NS5B structure with those having the bound inhibitors present show that residues Pro495 to Arg505 (the N terminus of the "T" helix) exhibit some of the largest changes. It has been reported that Pro495, Pro496, Val499 and Arg503 are part of the guanosine triphosphate (GTP) specific allosteric binding site located in close proximity to our binding site. It has also been reported that the introduction of mutations to key residues in this region (i.e. Val499Gly) ablate in vivo sub-genomic HCV RNA replication. The details of NS5B polymerase/inhibitor binding interactions coupled with the observed induced conformational changes provide new insights into the design of novel NNIs of HCV.

Non-nucleoside inhibitors binding to hepatitis C virus NS5B polymerase reveal a novel mechanism of inhibition.,Biswal BK, Wang M, Cherney MM, Chan L, Yannopoulos CG, Bilimoria D, Bedard J, James MN J Mol Biol. 2006 Aug 4;361(1):33-45. Epub 2006 Jun 16. PMID:16828488<ref>PMID:16828488</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2d3u" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Hepacivirus C]]
[[Category: Large Structures]]
[[Category: Bedard J]]
[[Category: Bilimoria D]]
[[Category: Biswal BK]]
[[Category: Chan L]]
[[Category: Cherney MM]]
[[Category: James MNG]]
[[Category: Wang M]]
[[Category: Yannopoulos CG]]