View source for 5hmw


==Dengue serotype 3 RNA-dependent RNA polymerase bound to compound 5==
<StructureSection load='5hmw' size='340' side='right' caption='[[5hmw]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5hmw]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HMW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HMW FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LNW:2,2-BIPHENYL-3,5-DIYLDIACETIC+ACID'>LNW</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">[[5hmx|5hmx]], [[5hmy|5hmy]], [[5hmz|5hmz]], [[5hn0|5hn0]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </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=5hmw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hmw OCA], [http://pdbe.org/5hmw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hmw RCSB], [http://www.ebi.ac.uk/pdbsum/5hmw PDBsum]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/Q6DLV0_9FLAV Q6DLV0_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:SAAS000336_004_099774] 
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== Publication Abstract from PubMed ==
The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis' fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a &gt;1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes.

Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design.,Yokokawa F, Nilar S, Noble CG, Lim SP, Rao R, Tania S, Wang G, Lee G, Hunziker J, Karuna R, Manjunatha U, Shi PY, Smith PW J Med Chem. 2016 Apr 28;59(8):3935-52. doi: 10.1021/acs.jmedchem.6b00143. Epub, 2016 Apr 8. PMID:26984786<ref>PMID:26984786</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
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</StructureSection>
[[Category: RNA-directed RNA polymerase]]
[[Category: Noble, C G]]
[[Category: Inhibitor complex polymerase]]
[[Category: Transferase-transferase inhibitor complex]]