4j93

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

spinqualitylabelsall models 4j93, resolution 1.74Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4j93 is a 1 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 0OE, 1JR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 PubMed The identification of novel antiretroviral agents is required to provide alternative treatment options for HIV-1 infected patients. The screening of a phenotypic cell-based viral replication assay led to the identification of a novel class of 4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one (or pyrrolopyrazolone) HIV-1 inhibitors, exemplified by two compounds: BI-1 and BI-2. These compounds inhibited early post-entry stages of viral replication at a step(s) following reverse transcription but prior to 2-LTR circle formation, suggesting that they may block nuclear targeting of the pre-integration complex. Selection of viruses resistant to BI-2 revealed that substitutions at residues A105 and T107 within the CA amino-terminal domain (CANTD) conferred high-level resistance to both compounds, implicating CA as the antiviral target. Direct binding of BI-1 and/or BI-2 to CANTD was demonstrated using isothermal titration calorimetry and NMR chemical shift titration analyses. A high resolution crystal structure of the BI-1:CANTD complex revealed that the inhibitor bound within a recently identified inhibitor binding pocket (CANTD site 2) between CA helices 4, 5 and 7, on the surface of the CANTD, that also corresponds to the binding site for the host factor, CPSF-6. The functional consequences of BI-1 and BI-2 binding differ from previously characterized inhibitors that bind the same site since the BI compounds did not inhibit reverse transcription but stabilized preassembled CA complexes. Hence, this new class of antiviral compounds binds CA and may inhibit viral replication by stabilizing the viral capsid. Discovery of Novel Small Molecule HIV-1 Replication Inhibitors that Stabilize Capsid Complexes.,Lamorte L, Titolo S, Lemke CT, Goudreau N, Mercier JF, Wardrop E, Shah VB, von Schwedler UK, Langelier C, Banik SS, Aiken C, Sundquist WI, Mason SW Antimicrob Agents Chemother. 2013 Jul 1. PMID:23817385 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Gag polyprotein 3D structures Virus coat proteins 3D structures

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