3is9
Crystal structure of the HIV-1 reverse transcriptase (RT) in complex with the alkenyldiarylmethane (ADAM) Non-nucleoside RT Inhibitor dimethyl 3,3'-(6-methoxy-6-oxohex-1-ene-1,1-diyl)bis(5-cyano-6-methoxybenzoate).Crystal structure of the HIV-1 reverse transcriptase (RT) in complex with the alkenyldiarylmethane (ADAM) Non-nucleoside RT Inhibitor dimethyl 3,3'-(6-methoxy-6-oxohex-1-ene-1,1-diyl)bis(5-cyano-6-methoxybenzoate).
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedTwo crystal structures have been solved for separate complexes of alkenyldiarylmethane (ADAM) nonnucleoside reverse transcriptase inhibitors (NNRTI) 3 and 4 with HIV-1 reverse transcriptase (RT). The structures reveal inhibitor binding is exclusively hydrophobic in nature and the shape of the inhibitor-bound NNRTI binding pocket is unique among other reported inhibitor-RT crystal structures. Primarily, ADAMs 3 and 4 protrude from a large gap in the back side of the binding pocket, placing portions of the inhibitors unusually close to the polymerase active site and allowing 3 to form a weak hydrogen bond with Lys223. The lack of additional stabilizing interactions, beyond the observed hydrophobic surface contacts, between 4 and RT is quite perplexing given the extreme potency of the compound (IC(50) </= 1 nM). ADAM 4 was designed to be hydrolytically stable in blood plasma, and an investigation of its hydrolysis in rat plasma demonstrated it has a significantly prolonged half-life in comparison to ADAM lead compounds 1 and 2. Crystallographic study of a novel subnanomolar inhibitor provides insight on the binding interactions of alkenyldiarylmethanes with human immunodeficiency virus-1 reverse transcriptase.,Cullen MD, Ho WC, Bauman JD, Das K, Arnold E, Hartman TL, Watson KM, Buckheit RW, Pannecouque C, De Clercq E, Cushman M J Med Chem. 2009 Oct 22;52(20):6467-73. PMID:19775161[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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