4CDU

Crystal structure of human Enterovirus 71 in complex with the uncoating inhibitor GPP3

4CDU の概要

• エントリーDOI: 10.2210/pdb4cdu/pdb
• 関連するPDBエントリー: 4CDQ 4CDW 4CDX 4CEW 4CEY
• 分子名称: VP1, VP2, VP3, ... (8 entities in total)
• 機能のキーワード: virus, hand-foot-and-mouth disease, enterovirus uncoating, inhibitor
• 由来する生物種: ENTEROVIRUS A71; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 94901.33

構造登録者

De Colibus, L.,Wang, X.,Spyrou, J.A.B.,Kelly, J.,Ren, J.,Grimes, J.,Puerstinger, G.,Stonehouse, N.,Walter, T.S.,Hu, Z.,Wang, J.,Li, X.,Peng, W.,Rowlands, D.,Fry, E.E.,Rao, Z.,Stuart, D.I. (登録日: 2013-11-06, 公開日: 2014-02-12, 最終更新日: 2024-05-08)

主引用文献

De Colibus, L.,Wang, X.,Spyrou, J.A.B.,Kelly, J.,Ren, J.,Grimes, J.,Puerstinger, G.,Stonehouse, N.,Walter, T.S.,Hu, Z.,Wang, J.,Li, X.,Peng, W.,Rowlands, D.J.,Fry, E.E.,Rao, Z.,Stuart, D.I.
More-Powerful Virus Inhibitors from Structure-Based Analysis of Hev71 Capsid-Binding Molecules
Nat.Struct.Mol.Biol., 21:282-, 2014

PubMed Abstract: 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.

PubMed: 24509833
DOI: 10.1038/NSMB.2769

実験手法

X-RAY DIFFRACTION (2.8 Å)