This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

3rc5

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 16:48, 4 August 2016

Molecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A protease

Structural highlights

3rc5 is a 2 chain structure with sequence from Hepatitis c virus subtype 1a. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:
Related:	3rc6, 3rc4
Gene:	NS3 (Hepatitis C virus subtype 1a)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MAVS_HUMAN] Required for innate immune defense against viruses. Acts downstream of DDX58/RIG-I and IFIH1/MDA5, which detect intracellular dsRNA produced during viral replication, to coordinate pathways leading to the activation of NF-kappa-B, IRF3 and IRF7, and to the subsequent induction of antiviral cytokines such as IFN-beta and RANTES (CCL5). Peroxisomal and mitochondrial MAVS act sequentially to create an antiviral cellular state. Upon viral infection, peroxisomal MAVS induces the rapid interferon-independent expression of defense factors that provide short-term protection, whereas mitochondrial MAVS activates an interferon-dependent signaling pathway with delayed kinetics, which amplifies and stabilizes the antiviral response. May activate the same pathways following detection of extracellular dsRNA by TLR3. May protect cells from apoptosis.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Hepatitis C NS3/4A protease is a prime therapeutic target responsible for cleaving the viral polyprotein at junctions 3-4A, 4A4B, 4B5A and 5A5B, and two host-cell adapter proteins of the innate immune response, TRIF and MAVS. In this study, NS3/4A crystal structures of both host-cell cleavage sites are determined and compared to the crystal structures of viral substrates. Two distinct protease conformations are observed and correlate with substrate specificity: (1) 3-4A, 4A4B, 5A5B and MAVS, which are processed more efficiently by the protease, form extensive electrostatic networks when in complex with the protease and (2) TRIF and 4B5A, which contain polyproline motifs in their full-length sequences, do not form electrostatic networks in their crystal complexes. These findings provide mechanistic insights into NS3/4A substrate recognition, which may assist in a more rational approach to inhibitor design in the face of the rapid acquisition of resistance.

Molecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A protease.,Romano KP, Laine JM, Deveau LM, Cao H, Massi F, Schiffer CA J Virol. 2011 Apr 20. PMID:21507982^[7]

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

References

↑ Seth RB, Sun L, Ea CK, Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005 Sep 9;122(5):669-82. PMID:16125763 doi:10.1016/j.cell.2005.08.012
↑ Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005 Sep 16;19(6):727-40. PMID:16153868 doi:S1097-2765(05)01556-X
↑ Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp J. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005 Oct 20;437(7062):1167-72. Epub 2005 Sep 21. PMID:16177806 doi:nature04193
↑ Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 2005 Oct;6(10):981-8. Epub 2005 Aug 28. PMID:16127453 doi:10.1038/ni1243
↑ Chiu YH, Macmillan JB, Chen ZJ. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell. 2009 Aug 7;138(3):576-91. doi: 10.1016/j.cell.2009.06.015. Epub 2009 Jul, 23. PMID:19631370 doi:10.1016/j.cell.2009.06.015
↑ Dixit E, Boulant S, Zhang Y, Lee AS, Odendall C, Shum B, Hacohen N, Chen ZJ, Whelan SP, Fransen M, Nibert ML, Superti-Furga G, Kagan JC. Peroxisomes are signaling platforms for antiviral innate immunity. Cell. 2010 May 14;141(4):668-81. doi: 10.1016/j.cell.2010.04.018. Epub 2010 May, 6. PMID:20451243 doi:10.1016/j.cell.2010.04.018
↑ Romano KP, Laine JM, Deveau LM, Cao H, Massi F, Schiffer CA. Molecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A protease. J Virol. 2011 Apr 20. PMID:21507982 doi:10.1128/JVI.00377-11

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3rc5"

@@ Line 1: / Line 1: @@
 ==Molecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A protease==
 <StructureSection load='3rc5' size='340' side='right' caption='[[3rc5]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3rc6|3rc6]], [[3rc4|3rc4]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=31646 Hepatitis C virus subtype 1a])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3rc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rc5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3rc5 RCSB], [http://www.ebi.ac.uk/pdbsum/3rc5 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3rc5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rc5 OCA], [http://pdbe.org/3rc5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3rc5 RCSB], [http://www.ebi.ac.uk/pdbsum/3rc5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3rc5 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3rc5" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

3rc5

From Proteopedia

Revision as of 16:48, 4 August 2016

Molecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A protease

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox