4INB

Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With benzodiazepine Inhibitor

4INB の概要

• エントリーDOI: 10.2210/pdb4inb/pdb
• 関連するPDBエントリー: 4E91 4E92
• 分子名称: Gag protein, (3Z)-3-{[(2-methoxyethyl)amino]methylidene}-1-methyl-5-phenyl-7-(trifluoromethyl)-1H-1,5-benzodiazepine-2,4(3H,5H)-dione, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: structural protein, capsid, viral protein, viral protein-viral protein inhibitor complex, viral protein/viral protein inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: Capsid protein p24: Virion (By similarity). Matrix protein p17: Virion (By similarity). Nucleocapsid protein p7: Virion (By similarity): Q79791
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 16646.96

構造登録者

Coulombe, R. (登録日: 2013-01-04, 公開日: 2013-02-27, 最終更新日: 2024-02-28)

主引用文献

Goudreau, N.,Coulombe, R.,Faucher, A.M.,Grand-Maitre, C.,Lacoste, J.E.,Lemke, C.T.,Malenfant, E.,Bousquet, Y.,Fader, L.,Simoneau, B.,Mercier, J.F.,Titolo, S.,Mason, S.W.
Monitoring Binding of HIV-1 Capsid Assembly Inhibitors Using (19) F Ligand-and (15) N Protein-Based NMR and X-ray Crystallography: Early Hit Validation of a Benzodiazepine Series.
Chemmedchem, 8:405-414, 2013

PubMed Abstract: The emergence of resistance to existing classes of antiretroviral drugs underlines the need to find novel human immunodeficiency virus (HIV)-1 targets for drug discovery. The viral capsid protein (CA) represents one such potential target. Recently, a series of benzodiazepine inhibitors was identified via high-throughput screening using an in vitro capsid assembly assay (CAA). Here, we demonstrate how a combination of NMR and X-ray co-crystallography allowed for the rapid characterization of the early hits from this inhibitor series. Ligand-based (19)F NMR was used to confirm inhibitor binding specificity and reversibility as well as to identify the N-terminal domain of the capsid (CA(NTD)) as its molecular target. Protein-based NMR ((1)H and (15)N chemical shift perturbation analysis) identified key residues within the CA(NTD) involved in inhibitor binding, while X-ray co-crystallography confirmed the inhibitor binding site and its binding mode. Based on these results, two conformationally restricted cyclic inhibitors were designed to further validate the possible binding modes. These studies were crucial to early hit confirmation and subsequent lead optimization.

PubMed: 23401268
DOI: 10.1002/cmdc.201200580

実験手法

X-RAY DIFFRACTION (1.8 Å)