4cew

Crystal structure of human Enterovirus 71 in complex with the uncoating inhibitor ALD

spinqualitylabelsall models 4cew, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4cew is a 4 chain structure with sequence from Ev-71. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 7J5 Related: 4cdq, 4cdu, 4cdw, 4cdx, 4cey Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [B2ZUN0_9ENTO] Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).[SAAS:SAAS000199_004_016611] Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity).[SAAS:SAAS000199_004_042266] RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).[SAAS:SAAS000199_004_010047] Publication Abstract from PubMed Enterovirus 71 (HEV71) epidemics in children and infants result mainly in mild symptoms; however, especially in the Asia-Pacific region, infection can be fatal. At present, no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Analysis of complexes with four 3-(4-pyridyl)-2-imidazolidinone derivatives with varying anti-HEV71 activities pinpointed key structure-activity correlates. We then identified additional potentially beneficial substitutions, developed methods to reliably triage compounds by quantum mechanics-enhanced ligand docking and synthesized two candidates. Structural analysis and in vitro assays confirmed the predicted binding modes and their ability to block viral infection. One ligand (with IC50 of 25 pM) is an order of magnitude more potent than the best previously reported inhibitor and is also more soluble. Our approach may be useful in the design of effective drugs for enterovirus infections. More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules.,De Colibus L, Wang X, Spyrou JA, Kelly J, Ren J, Grimes J, Puerstinger G, Stonehouse N, Walter TS, Hu Z, Wang J, Li X, Peng W, Rowlands DJ, Fry EE, Rao Z, Stuart DI Nat Struct Mol Biol. 2014 Feb 9. doi: 10.1038/nsmb.2769. PMID:24509833 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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