2XDE

Crystal structure of the complex of PF-3450074 with an engineered HIV capsid N terminal domain

Summary for 2XDE

• Entry DOI: 10.2210/pdb2xde/pdb
• Descriptor: GAG POLYPROTEIN, N-METHYL-NALPHA-[(2-METHYL-1H-INDOL-3-YL)ACETYL]-N-PHENYL-L-PHENYLALANINAMIDE (3 entities in total)
• Functional Keywords: aids, viral protein
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS 1
• Total number of polymer chains: 2
• Total formula weight: 33286.03

Authors

Brown, D.G.,Irving, S.L.,Anderson, M.,Bazin, R. (deposition date: 2010-04-30, release date: 2010-12-22, Last modification date: 2024-05-01)

Primary citation

Blair, W.S.,Pickford, C.,Irving, S.L.,Brown, D.G.,Anderson, M.,Bazin, R.,Cao, J.,Ciaramella, G.,Isaacson, J.,Jackson, L.,Hunt, R.,Kjerrstrom, A.,Nieman, J.,Patick, A.K.,Perros, M.,Scott, A.D.,Whitby, K.,Wu, H.,Butler, S.L.
HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention.
Plos Pathog., 6:E1220-, 2010

PubMed Abstract: Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.

PubMed: 21170360
DOI: 10.1371/JOURNAL.PPAT.1001220

Experimental method

X-RAY DIFFRACTION (1.4 Å)