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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/A0A097PIE2_9FLAV A0A097PIE2_9FLAV] Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host immune response.[ARBA:ARBA00024317]  Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[ARBA:ARBA00003504]  Serine protease subunit NS2B: Required cofactor for the serine protease function of NS3.[PROSITE-ProRule:PRU00859]
[https://www.uniprot.org/uniprot/A0A097PIE2_9FLAV A0A097PIE2_9FLAV] Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host immune response.[ARBA:ARBA00024317]  Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[ARBA:ARBA00003504]  Serine protease subunit NS2B: Required cofactor for the serine protease function of NS3.[PROSITE-ProRule:PRU00859]
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== Publication Abstract from PubMed ==
Flaviviruses comprise major emerging pathogens such as dengue virus (DENV) or Zika virus (ZIKV). The flavivirus RNA genome is replicated by the RNA-dependent-RNA polymerase (RdRp) domain of non-structural protein 5 (NS5). This essential enzymatic activity renders the RdRp attractive for antiviral therapy. NS5 synthesizes viral RNA via a "de novo" initiation mechanism. Crystal structures of the flavivirus RdRp revealed a "closed" conformation reminiscent of a pre-initiation state, with a well ordered priming loop that extrudes from the thumb subdomain into the dsRNA exit tunnel, close to the "GDD" active site. To-date, no allosteric pockets have been identified for the RdRp, and compound screening campaigns did not yield suitable drug candidates. Using fragment-based screening via X-ray crystallography, we found a fragment that bound to a pocket of the apo-DENV RdRp close to its active site (termed "N pocket"). Structure-guided improvements yielded DENV pan-serotype inhibitors of the RdRp de novo initiation activity with nano-molar potency that also impeded elongation activity at micro-molar concentrations. Inhibitors exhibited mixed inhibition kinetics with respect to competition with the RNA or GTP substrate. The best compounds have EC50 values of 1-2 muM against all four DENV serotypes in cell culture assays. Genome-sequencing of compound-resistant DENV replicons, identified amino acid changes that mapped to the N pocket. Since inhibitors bind at the thumb/palm interface of the RdRp, this class of compounds is proposed to hinder RdRp conformational changes during its transition from initiation to elongation. This is the first report of a class of pan-serotype and cell-active DENV RdRp inhibitors. Given the evolutionary conservation of residues lining the N pocket, these molecules offer insights to treat other serious conditions caused by flaviviruses.
Potent Allosteric Dengue Virus NS5 Polymerase Inhibitors: Mechanism of Action and Resistance Profiling.,Lim SP, Noble CG, Seh CC, Soh TS, El Sahili A, Chan GK, Lescar J, Arora R, Benson T, Nilar S, Manjunatha U, Wan KF, Dong H, Xie X, Shi PY, Yokokawa F PLoS Pathog. 2016 Aug 8;12(8):e1005737. doi: 10.1371/journal.ppat.1005737., eCollection 2016 Aug. PMID:27500641<ref>PMID:27500641</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
==See Also==
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
== References ==
<references/>
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__TOC__
</StructureSection>
</StructureSection>

Latest revision as of 15:39, 6 March 2024

Co-Crystal Structure of Dengue Virus Serotype 2 RNA Dependent RNA Polymerase with Compound 27Co-Crystal Structure of Dengue Virus Serotype 2 RNA Dependent RNA Polymerase with Compound 27

Structural highlights

5k5m is a 1 chain structure with sequence from Dengue virus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.01Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A0A097PIE2_9FLAV Component of the viral RNA replication complex that functions in virion assembly and antagonizes the host immune response.[ARBA:ARBA00024317] Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[ARBA:ARBA00003504] Serine protease subunit NS2B: Required cofactor for the serine protease function of NS3.[PROSITE-ProRule:PRU00859]

See Also

5k5m, resolution 2.01Å

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OCA
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