4e92 | pdb_00004e92
Crystal Structure of the N-Terminal Domain of HIV-1 Capsid in Complex With Inhibitor BM4
Structural highlights
Function[Q79791_9HIV1] Capsid protein p24 forms the conical core of the virus that encapsulates the genomic RNA-nucleocapsid complex (By similarity).[SAAS:SAAS000071_004_008806] Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers (By similarity).[SAAS:SAAS000071_004_011858] Publication Abstract from PubMedThe emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral CA (capsid) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids in vitro and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an in vitro capsid assembly assay based on association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM) resulted in compounds with potent antiviral activity against wild type and drug-resistant HIV-1. NMR spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors, but is expanded significantly by these new, more potent CA inhibitors. Virus release and EM studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action. Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the N-terminal domain of the viral CA protein.,Lemke CT, Titolo S, von Schwedler U, Goudreau N, Mercier JF, Wardrop E, Faucher AM, Coulombe R, Banik SS, Fader L, Gagnon A, Kawai SH, Rancourt J, Tremblay M, Yoakim C, Simoneau B, Archambault J, Sundquist WI, Mason SW J Virol. 2012 Apr 11. PMID:22496222[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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