4INB

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

Summary for 4INB

• Entry DOI: 10.2210/pdb4inb/pdb
• Related: 4E91 4E92
• Descriptor: 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)
• Functional Keywords: structural protein, capsid, viral protein, viral protein-viral protein inhibitor complex, viral protein/viral protein inhibitor
• Biological source: Human immunodeficiency virus 1
• Cellular location: Capsid protein p24: Virion (By similarity). Matrix protein p17: Virion (By similarity). Nucleocapsid protein p7: Virion (By similarity): Q79791
• Total number of polymer chains: 1
• Total formula weight: 16646.96

Authors

Coulombe, R. (deposition date: 2013-01-04, release date: 2013-02-27, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)