1tv6
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HIV-1 Reverse Transcriptase Complexed with CP-94,707
OverviewOverview
We have determined the crystal structure of the HIV type 1 reverse, transcriptase complexed with CP-94,707, a new nonnucleoside reverse, transcriptase inhibitor (NNRTI), to 2.8-A resolution. In addition to, inhibiting the wild-type enzyme, this compound inhibits mutant enzymes, that are resistant to inhibition by nevirapine, efavirenz, and, delaviridine. In contrast to other NNRTI complexes where tyrosines 181 and, 188 are pointing toward the enzyme active site, the binding pocket in this, complex has the tyrosines pointing the opposite direction, as in the, unliganded protein structure, to accommodate CP-94,707. This conformation, of the pocket has not been observed previously in NNRTI complexes and, substantially alters the shape and surface features that are available for, interactions with the inhibitor. One ring of CP-94,707 makes extensive, stacking interactions with tryptophan 229, one of the few residues in the, NNRTI-binding pocket that cannot readily mutate to give rise to drug, resistance. In this conformation of the pocket, mutations of tyrosines 181, and 188 are less likely to disrupt inhibitor binding. Modeling the, asparagine mutation of lysine 103 shows that a hydrogen bond between it, and tyrosine 188 could form as readily in the CP-94,707 complex as it does, in the apoenzyme structure, providing an explanation for the activity of, this inhibitor against this clinically important mutant.
About this StructureAbout this Structure
1TV6 is a Protein complex structure of sequences from Human immunodeficiency virus type 1 (isolate bh10) with CP9 as ligand. Active as Sulfate adenylyltransferase, with EC number 2.7.7.4 Full crystallographic information is available from OCA.
ReferenceReference
Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors., Pata JD, Stirtan WG, Goldstein SW, Steitz TA, Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10548-53. Epub 2004 Jul 12. PMID:15249669
Page seeded by OCA on Thu Nov 8 14:31:52 2007