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'''CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-1 (PETT131A94)''' | '''CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-1 (PETT131A94)''' | ||
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[[Category: Stuart, D I.]] | [[Category: Stuart, D I.]] | ||
[[Category: Warren, J.]] | [[Category: Warren, J.]] | ||
[[Category: | [[Category: Drug design]] | ||
[[Category: | [[Category: Hiv-1 reverse transcriptase aid]] | ||
[[Category: | [[Category: Non-nucleoside inhibitor]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 14:15:47 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 14:15, 2 May 2008
CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-1 (PETT131A94)
OverviewOverview
Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for HIV-1 RT and demonstrate minimal inhibition of HIV-2 RT. However, we report that members of the phenylethylthiazolylthiourea (PETT) series of non-nucleoside reverse transcriptase inhibitors showing high potency against HIV-1 RT have varying abilities to inhibit HIV-2 RT. Thus, PETT-1 inhibits HIV-1 RT with an IC(50) of 6 nM but shows only weak inhibition of HIV-2 RT, whereas PETT-2 retains similar potency against HIV-1 RT (IC(50) of 5 nM) and also inhibits HIV-2 RT (IC(50) of 2.2 microM). X-ray crystallographic structure determinations of PETT-1 and PETT-2 in complexes with HIV-1 RT reveal the compounds bind in an overall similar conformation albeit with some differences in their interactions with the protein. To investigate whether PETT-2 could be acting at a different site on HIV-2 RT (e.g. the dNTP or template primer binding site), we compared modes of inhibition for PETT-2 against HIV-1 and HIV-2 RT. PETT-2 was a noncompetitive inhibitor with respect to the dGTP substrate for both HIV-1 and HIV-2 RTs. PETT-2 was also a noncompetitive inhibitor with respect to a poly(rC).(dG) template primer for HIV-2 RT. These results are consistent with PETT-2 binding in corresponding pockets in both HIV-1 and HIV-2 RT with amino acid sequence differences in HIV-2 RT affecting the binding of PETT-2 compared with PETT-1.
About this StructureAbout this Structure
1DTQ is a Protein complex structure of sequences from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
ReferenceReference
Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses., Ren J, Diprose J, Warren J, Esnouf RM, Bird LE, Ikemizu S, Slater M, Milton J, Balzarini J, Stuart DI, Stammers DK, J Biol Chem. 2000 Feb 25;275(8):5633-9. PMID:10681546 Page seeded by OCA on Fri May 2 14:15:47 2008