1dtt
From Proteopedia
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CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-2 (PETT130A94)
Overview
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 Structure
1DTT is a Protein complex structure of sequences from Human immunodeficiency virus 1 with FTC as ligand. Full crystallographic information is available from OCA.
Reference
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
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