3lkw

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==Crystal Structure of Dengue Virus 1 NS2B/NS3 protease active site mutant==
==Crystal Structure of Dengue Virus 1 NS2B/NS3 protease active site mutant==
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<StructureSection load='3lkw' size='340' side='right' caption='[[3lkw]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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<StructureSection load='3lkw' size='340' side='right'caption='[[3lkw]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3lkw]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Dengue_virus_1 Dengue virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LKW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3LKW FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3lkw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Dengue_virus_1_Nauru/West_Pac/1974 Dengue virus 1 Nauru/West Pac/1974] and [https://en.wikipedia.org/wiki/Dengue_virus_1_Singapore/S275/1990 Dengue virus 1 Singapore/S275/1990]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3LKW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3LKW FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</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>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3l6p|3l6p]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NS2B/NS3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11053 Dengue virus 1])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3lkw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lkw OCA], [https://pdbe.org/3lkw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3lkw RCSB], [https://www.ebi.ac.uk/pdbsum/3lkw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3lkw ProSAT]</span></td></tr>
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<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=3lkw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3lkw OCA], [http://pdbe.org/3lkw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3lkw RCSB], [http://www.ebi.ac.uk/pdbsum/3lkw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3lkw ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/Q9J7C6_9FLAV Q9J7C6_9FLAV]] Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).[SAAS:SAAS026470_004_099774]
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[https://www.uniprot.org/uniprot/POLG_DEN1W POLG_DEN1W] Capsid protein C self-assembles to form an icosahedral capsid about 30 nm in diameter. The capsid encapsulates the genomic RNA (By similarity). prM acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is matured in the last step of virion assembly, presumably to avoid catastrophic activation of the viral fusion peptide induced by the acidic pH of the trans-Golgi network. After cleavage by host furin, the pr peptide is released in the extracellular medium and small envelope protein M and envelope protein E homodimers are dissociated (By similarity). Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity). Non-structural protein 1 is involved in virus replication and regulation of the innate immune response. Soluble and membrane-associated NS1 may activate human complement and induce host vascular leakage. This effect might explain the clinical manifestations of dengue hemorrhagic fever and dengue shock syndrome (By similarity). Non-structural protein 2A may be involved viral RNA replication and capsid assembly (Potential). Non-structural protein 2B is a required cofactor for the serine protease function of NS3 (By similarity). Serine protease NS3 displays three enzymatic activities: serine protease, NTPase and RNA helicase. NS3 serine protease, in association with NS2B, performs its autocleavage and cleaves the polyprotein at dibasic sites in the cytoplasm: C-prM, NS2A-NS2B, NS2B-NS3, NS3-NS4A, NS4A-2K and NS4B-NS5. NS3 RNA helicase binds RNA and unwinds dsRNA in the 3' to 5' direction (By similarity). Non-structural protein 4A induces host endoplasmic reticulum membrane rearrangements leading to the formation of virus-induced membranous vesicles hosting the dsRNA and polymerase, functioning as a replication complex. NS4A might also regulate the ATPase activity of the NS3 helicase (By similarity). Peptide 2k functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter (By similarity). Non-structural protein 4B inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway (By similarity). RNA-directed RNA polymerase NS5 replicates the viral (+) and (-) genome, and performs the capping of genomes in the cytoplasm. NS5 methylates viral RNA cap at guanine N-7 and ribose 2'-O positions. Besides its role in genome replication, also prevents the establishment of cellular antiviral state by blocking the interferon-alpha/beta (IFN-alpha/beta) signaling pathway. Inhibits host TYK2 and STAT2 phosphorylation, thereby preventing activation of JAK-STAT signaling pathway (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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With an estimated 40% of the world population at risk, dengue poses a significant threat to human health, especially in tropical and subtropical regions. Preventative and curative efforts, such as vaccine development and drug discovery, face additional challenges due to the occurrence of four antigenically distinct serotypes of the causative dengue virus (DEN1 to -4). Complex immune responses resulting from repeat assaults by the different serotypes necessitate simultaneous targeting of all forms of the virus. One of the promising targets for drug development is the highly conserved two-component viral protease NS2B-NS3, which plays an essential role in viral replication by processing the viral precursor polyprotein into functional proteins. In this paper, we report the 2.1-A crystal structure of the DEN1 NS2B hydrophilic core (residues 49 to 95) in complex with the NS3 protease domain (residues 1 to 186) carrying an internal deletion in the N terminus (residues 11 to 20). While the overall folds within the protease core are similar to those of DEN2 and DEN4 proteases, the conformation of the cofactor NS2B is dramatically different from those of other flaviviral apoprotease structures. The differences are especially apparent within its C-terminal region, implicated in substrate binding. The structure reveals for the first time serotype-specific structural elements in the dengue virus family, with the reported alternate conformation resulting from a unique metal-binding site within the DEN1 sequence. We also report the identification of a 10-residue stretch within NS3pro that separates the substrate-binding function from the catalytic turnover rate of the enzyme. Implications for broad-spectrum drug discovery are discussed.
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Serotype-specific structural differences in the protease-cofactor complexes of the dengue virus family.,Chandramouli S, Joseph JS, Daudenarde S, Gatchalian J, Cornillez-Ty C, Kuhn P J Virol. 2010 Mar;84(6):3059-67. Epub 2009 Dec 30. PMID:20042502<ref>PMID:20042502</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3lkw" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Nonstructural protein|Nonstructural protein]]
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*[[Nonstructural protein 3D structures|Nonstructural protein 3D structures]]
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== References ==
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*[[Virus protease 3D structures|Virus protease 3D structures]]
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Dengue virus 1]]
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[[Category: Dengue virus 1 Nauru/West Pac/1974]]
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[[Category: Chandramouli, S]]
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[[Category: Dengue virus 1 Singapore/S275/1990]]
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[[Category: Cornillez-Ty, C]]
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[[Category: Large Structures]]
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[[Category: Daudenarde, S]]
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[[Category: Chandramouli S]]
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[[Category: Gatchalian, J]]
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[[Category: Cornillez-Ty C]]
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[[Category: Joseph, J S]]
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[[Category: Daudenarde S]]
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[[Category: Kuhn, P]]
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[[Category: Gatchalian J]]
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[[Category: Hydrolase]]
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[[Category: Joseph JS]]
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[[Category: Ns2b cofactor]]
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[[Category: Kuhn P]]
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[[Category: Ns3 protease]]
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[[Category: Serine protease]]
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[[Category: Viral protease]]
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[[Category: Viral protein]]
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Current revision

Crystal Structure of Dengue Virus 1 NS2B/NS3 protease active site mutant

PDB ID 3lkw

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