3rc4: Difference between revisions
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==Molecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A protease== | |||
<StructureSection load='3rc4' size='340' side='right' caption='[[3rc4]], [[Resolution|resolution]] 1.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3rc4]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hepatitis_c_virus_subtype_1a Hepatitis c virus subtype 1a]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RC4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RC4 FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3rc6|3rc6]], [[3rc5|3rc5]]</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=3rc4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rc4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3rc4 RCSB], [http://www.ebi.ac.uk/pdbsum/3rc4 PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/TCAM1_HUMAN TCAM1_HUMAN]] Herpetic encephalitis. Herpes simplex encephalitis 4 (HSE4) [MIM:[http://omim.org/entry/614850 614850]]: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.<ref>PMID:22105173</ref> | [[http://www.uniprot.org/uniprot/TCAM1_HUMAN TCAM1_HUMAN]] Herpetic encephalitis. Herpes simplex encephalitis 4 (HSE4) [MIM:[http://omim.org/entry/614850 614850]]: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.<ref>PMID:22105173</ref> | ||
== Function == | |||
==Function== | |||
[[http://www.uniprot.org/uniprot/TCAM1_HUMAN TCAM1_HUMAN]] Involved in innate immunity against invading pathogens. Adapter used by TLR3 and TLR4 (through TICAM2) to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively.<ref>PMID:12471095</ref> <ref>PMID:12539043</ref> <ref>PMID:14739303</ref> | [[http://www.uniprot.org/uniprot/TCAM1_HUMAN TCAM1_HUMAN]] Involved in innate immunity against invading pathogens. Adapter used by TLR3 and TLR4 (through TICAM2) to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively.<ref>PMID:12471095</ref> <ref>PMID:12539043</ref> <ref>PMID:14739303</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:21507982</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Hepatitis c virus subtype 1a]] | [[Category: Hepatitis c virus subtype 1a]] | ||
[[Category: Romano, K P | [[Category: Romano, K P]] | ||
[[Category: Schiffer, C A | [[Category: Schiffer, C A]] | ||
[[Category: Chymotrypsin-like]] | [[Category: Chymotrypsin-like]] | ||
[[Category: Drug design]] | [[Category: Drug design]] | ||
Revision as of 13:48, 19 December 2014
Molecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A proteaseMolecular mechanisms of viral and host-cell substrate recognition by HCV NS3/4A protease
Structural highlights
Disease[TCAM1_HUMAN] Herpetic encephalitis. Herpes simplex encephalitis 4 (HSE4) [MIM:614850]: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.[1] Function[TCAM1_HUMAN] Involved in innate immunity against invading pathogens. Adapter used by TLR3 and TLR4 (through TICAM2) to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively.[2] [3] [4] Publication Abstract from PubMedHepatitis 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[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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