5FRO

Crystal structure of the Prototype Foamy Virus (PFV) intasome in complex with magnesium and the INSTI XZ446 (compound 4f)

5FRO の概要

• エントリーDOI: 10.2210/pdb5fro/pdb
• 関連するPDBエントリー: 5FRM 5FRN
• 分子名称: PFV INTEGRASE, 5'-D(*AP*TP*TP*GP*TP*CP*AP*TP*GP*GP*AP*AP*TP*TP *TP*CP*GP*CP*A)-3', 5'-D(*TP*GP*CP*GP*AP*AP*AP*TP*TP*CP*CP*AP*TP*GP *AP*CP*A)-3', ... (9 entities in total)
• 機能のキーワード: recombination, viral protein/dna, protein-dna complex, tetramer, dna integration, endonuclease, metal-binding, multifunctional enzyme, nuclease, nucleotidyltransferase, nucleus, transferase, viral nucleoprotein, virion, dna- binding, zinc binding, hhcc motif, viral protein, inhibitor, dna-binding protein-dna complex
• 由来する生物種: HUMAN SPUMARETROVIRUS (SFVCPZ(HU)); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 101537.19

構造登録者

Maskell, D.P.,Pye, V.E.,Cherepanov, P. (登録日: 2015-12-18, 公開日: 2016-02-17, 最終更新日: 2024-01-10)

主引用文献

Zhao, X.Z.,Smith, S.J.,Maskell, D.P.,Metifiot, M.,Pye, V.E.,Fesen, K.,Marchand, C.,Pommier, Y.,Cherepanov, P.,Hughes, S.H.,Burke, T.R.J.
HIV-1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases.
Acs Chem.Biol., 11:1074-, 2016

PubMed Abstract: HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance. We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations. We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3'-processing and the bound host DNA prior to strand transfer. Using this concept of "bi-substrate mimicry," we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy. Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.

PubMed: 26808478
DOI: 10.1021/ACSCHEMBIO.5B00948

実験手法

X-RAY DIFFRACTION (2.67 Å)