4a92: Difference between revisions
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[[ | ==Full-length HCV NS3-4A protease-helicase in complex with a macrocyclic protease inhibitor.== | ||
<StructureSection load='4a92' size='340' side='right' caption='[[4a92]], [[Resolution|resolution]] 2.73Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4a92]] 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=4A92 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A92 FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F9K:(1R,2R,2S,6S,24AS)-17-FLUORO-6-(1-METHYL-2-OXOPIPERIDINE-3-CARBOXAMIDO)-19,19-DIOXIDO-5,21,24-TRIOXO-2-VINYL-1,2,3,5,6,7,8,9,10,11,12,13,14,20,21,23,24,24A-OCTADECAHYDROSPIRO[BENZO[S]PYRROLO[2,1-G][1,2,5,8,18]THIATETRAAZACYCLOICOSINE-22,1-CYCLOPRO-2-CARBOXYLATEPAN]-2-YL+4-FLUOROISOINDOLINE'>F9K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]], [[2xwy|2xwy]], [[1csj|1csj]], [[2who|2who]], [[1nhv|1nhv]], [[2brl|2brl]], [[1gx5|1gx5]], [[2brk|2brk]], [[2ax0|2ax0]], [[2awz|2awz]], [[1quv|1quv]], [[1os5|1os5]]</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=4a92 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a92 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a92 RCSB], [http://www.ebi.ac.uk/pdbsum/4a92 PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Hepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C infection leads to serious liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV NS3 protein is essential for viral polyprotein processing and RNA replication and hence viral replication. It is composed of an N-terminal serine protease domain and a C-terminal helicase/NTPase domain. For full activity, the protease requires the NS4A protein as a cofactor. HCV NS3/4A protease is a prime target for developing direct-acting antiviral agents. First-generation NS3/4A protease inhibitors have recently been introduced into clinical practice, markedly changing HCV treatment options. To date, crystal structures of HCV NS3/4A protease inhibitors have only been reported in complex with the protease domain alone. Here, we present a unique structure of an inhibitor bound to the full-length, bifunctional protease-helicase NS3/4A and show that parts of the P4 capping and P2 moieties of the inhibitor interact with both protease and helicase residues. The structure sheds light on inhibitor binding to the more physiologically relevant form of the enzyme and supports exploring inhibitor-helicase interactions in the design of the next generation of HCV NS3/4A protease inhibitors. In addition, small angle X-ray scattering confirmed the observed protease-helicase domain assembly in solution. | |||
A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target.,Schiering N, D'Arcy A, Villard F, Simic O, Kamke M, Monnet G, Hassiepen U, Svergun DI, Pulfer R, Eder J, Raman P, Bodendorf U Proc Natl Acad Sci U S A. 2011 Dec 12. PMID:22160684<ref>PMID:22160684</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
*[[Helicase|Helicase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[ | |||
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[[Category: Hepatitis c virus]] | [[Category: Hepatitis c virus]] | ||
[[Category: Arcy, A D.]] | [[Category: Arcy, A D.]] | ||
Revision as of 10:22, 5 June 2014
Full-length HCV NS3-4A protease-helicase in complex with a macrocyclic protease inhibitor.Full-length HCV NS3-4A protease-helicase in complex with a macrocyclic protease inhibitor.
Structural highlights
Publication Abstract from PubMedHepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C infection leads to serious liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV NS3 protein is essential for viral polyprotein processing and RNA replication and hence viral replication. It is composed of an N-terminal serine protease domain and a C-terminal helicase/NTPase domain. For full activity, the protease requires the NS4A protein as a cofactor. HCV NS3/4A protease is a prime target for developing direct-acting antiviral agents. First-generation NS3/4A protease inhibitors have recently been introduced into clinical practice, markedly changing HCV treatment options. To date, crystal structures of HCV NS3/4A protease inhibitors have only been reported in complex with the protease domain alone. Here, we present a unique structure of an inhibitor bound to the full-length, bifunctional protease-helicase NS3/4A and show that parts of the P4 capping and P2 moieties of the inhibitor interact with both protease and helicase residues. The structure sheds light on inhibitor binding to the more physiologically relevant form of the enzyme and supports exploring inhibitor-helicase interactions in the design of the next generation of HCV NS3/4A protease inhibitors. In addition, small angle X-ray scattering confirmed the observed protease-helicase domain assembly in solution. A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target.,Schiering N, D'Arcy A, Villard F, Simic O, Kamke M, Monnet G, Hassiepen U, Svergun DI, Pulfer R, Eder J, Raman P, Bodendorf U Proc Natl Acad Sci U S A. 2011 Dec 12. PMID:22160684[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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