Structural highlights
5hmx is a 1 chain structure with sequence from Dengue virus 3. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , |
| Related: | 5hmw, 5hmy, 5hmz, 5hn0 |
| Activity: | RNA-directed RNA polymerase, with EC number 2.7.7.48 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[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]
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 >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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design. J Med Chem. 2016 Apr 28;59(8):3935-52. doi: 10.1021/acs.jmedchem.6b00143. Epub, 2016 Apr 8. PMID:26984786 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00143
