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[[Image:2who.png|left|200px]]
==CRYSTAL STRUCTURE OF HEPATITIS C VIRUS NS5B POLYMERASE FROM 1B GENOTYPE IN COMPLEX WITH A NON-NUCLEOSIDE INHIBITOR==
<StructureSection load='2who' size='340' side='right' caption='[[2who]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2who]] is a 2 chain structure with sequence 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=2WHO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WHO FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=VGI:2-(3-BROMOPHENYL)-6-[(2-HYDROXYETHYL)AMINO]-1H-BENZO[DE]ISOQUINOLINE-1,3(2H)-DIONE'>VGI</scene><br>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nhu|1nhu]], [[2i1r|2i1r]], [[2wcx|2wcx]], [[1jxp|1jxp]], [[1gx6|1gx6]], [[2jc1|2jc1]], [[8ohm|8ohm]], [[1c2p|1c2p]], [[1a1q|1a1q]], [[1cu1|1cu1]], [[1bt7|1bt7]], [[2jc0|2jc0]], [[2ax1|2ax1]], [[1ns3|1ns3]], [[1csj|1csj]], [[1nhv|1nhv]], [[1gx5|1gx5]], [[2brk|2brk]], [[2brl|2brl]], [[2ax0|2ax0]], [[2awz|2awz]], [[1quv|1quv]], [[1os5|1os5]]</td></tr>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </span></td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2who FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2who OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2who RCSB], [http://www.ebi.ac.uk/pdbsum/2who PDBsum]</span></td></tr>
<table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two different HCV replicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Polio-pol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the DeltaC55-1b and DeltaC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.


{{STRUCTURE_2who|  PDB=2who  |  SCENE=  }}
Identification and Biological Evaluation of a Series of 1H-Benzo[de]isoquinoline-1,3(2H)-diones as Hepatitis C Virus NS5B Polymerase Inhibitors (double dagger).,Ontoria JM, Rydberg EH, Di Marco S, Tomei L, Attenni B, Malancona S, Martin Hernando JI, Gennari N, Koch U, Narjes F, Rowley M, Summa V, Carroll SS, Olsen DB, De Francesco R, Altamura S, Migliaccio G, Carfi A J Med Chem. 2009 Aug 27;52(16):5217-27. PMID:19877603<ref>PMID:19877603</ref>


===CRYSTAL STRUCTURE OF HEPATITIS C VIRUS NS5B POLYMERASE FROM 1B GENOTYPE IN COMPLEX WITH A NON-NUCLEOSIDE INHIBITOR===
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
{{ABSTRACT_PUBMED_19877603}}
 
==About this Structure==
[[2who]] is a 2 chain structure with sequence 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=2WHO OCA].


==See Also==
==See Also==
*[[RNA polymerase|RNA polymerase]]
*[[RNA polymerase|RNA polymerase]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:019877603</ref><references group="xtra"/>
__TOC__
</StructureSection>
[[Category: Hepatitis c virus]]
[[Category: Hepatitis c virus]]
[[Category: RNA-directed RNA polymerase]]
[[Category: RNA-directed RNA polymerase]]

Revision as of 03:58, 2 October 2014

CRYSTAL STRUCTURE OF HEPATITIS C VIRUS NS5B POLYMERASE FROM 1B GENOTYPE IN COMPLEX WITH A NON-NUCLEOSIDE INHIBITORCRYSTAL STRUCTURE OF HEPATITIS C VIRUS NS5B POLYMERASE FROM 1B GENOTYPE IN COMPLEX WITH A NON-NUCLEOSIDE INHIBITOR

Structural highlights

2who is a 2 chain structure with sequence from Hepatitis c virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Related:1nhu, 2i1r, 2wcx, 1jxp, 1gx6, 2jc1, 8ohm, 1c2p, 1a1q, 1cu1, 1bt7, 2jc0, 2ax1, 1ns3, 1csj, 1nhv, 1gx5, 2brk, 2brl, 2ax0, 2awz, 1quv, 1os5
Activity:RNA-directed RNA polymerase, with EC number 2.7.7.48
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two different HCV replicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Polio-pol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the DeltaC55-1b and DeltaC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.

Identification and Biological Evaluation of a Series of 1H-Benzo[de]isoquinoline-1,3(2H)-diones as Hepatitis C Virus NS5B Polymerase Inhibitors (double dagger).,Ontoria JM, Rydberg EH, Di Marco S, Tomei L, Attenni B, Malancona S, Martin Hernando JI, Gennari N, Koch U, Narjes F, Rowley M, Summa V, Carroll SS, Olsen DB, De Francesco R, Altamura S, Migliaccio G, Carfi A J Med Chem. 2009 Aug 27;52(16):5217-27. PMID:19877603[1]

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

See Also

References

  1. ↑ Ontoria JM, Rydberg EH, Di Marco S, Tomei L, Attenni B, Malancona S, Martin Hernando JI, Gennari N, Koch U, Narjes F, Rowley M, Summa V, Carroll SS, Olsen DB, De Francesco R, Altamura S, Migliaccio G, Carfi A. Identification and Biological Evaluation of a Series of 1H-Benzo[de]isoquinoline-1,3(2H)-diones as Hepatitis C Virus NS5B Polymerase Inhibitors (double dagger). J Med Chem. 2009 Aug 27;52(16):5217-27. PMID:19877603 doi:10.1021/jm900517t

2who, resolution 2.00Å

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