1dtq: Difference between revisions

Revision as of 13:20, 21 February 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 with as ligand. 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

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-[[Image:1dtq.gif|left|200px]]<br />
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 caption="1dtq, resolution 2.8&Aring;" />
 '''CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-1 (PETT131A94)'''<br />
 ==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.
+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==
-DTQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with FPT as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1DTQ OCA].
+DTQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with <scene name='pdbligand=FPT:'>FPT</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DTQ OCA].
 ==Reference==
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 [[Category: Protein complex]]
 [[Category: Balzarini, J.]]
-[[Category: Bird, L.E.]]
+[[Category: Bird, L E.]]
 [[Category: Diprose, J.]]
-[[Category: Esnouf, R.M.]]
+[[Category: Esnouf, R M.]]
 [[Category: Ikemizu, S.]]
 [[Category: Milton, J.]]
 [[Category: Ren, J.]]
 [[Category: Slater, M.]]
-[[Category: Stammers, D.K.]]
+[[Category: Stammers, D K.]]
-[[Category: Stuart, D.I.]]
+[[Category: Stuart, D I.]]
 [[Category: Warren, J.]]
 [[Category: FPT]]
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 [[Category: non-nucleoside inhibitor]]
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