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1dtt
From Proteopedia
(New page: 200px<br /> <applet load="1dtt" size="450" color="white" frame="true" align="right" spinBox="true" caption="1dtt, resolution 3.0Å" /> '''CRYSTAL STRUCTURE OF...) |
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| - | [[Image:1dtt.gif|left|200px]]<br /> | + | [[Image:1dtt.gif|left|200px]]<br /><applet load="1dtt" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1dtt" size=" | + | |
caption="1dtt, resolution 3.0Å" /> | caption="1dtt, resolution 3.0Å" /> | ||
'''CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-2 (PETT130A94)'''<br /> | '''CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-2 (PETT130A94)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Most non-nucleoside reverse transcriptase (RT) inhibitors are specific for | + | 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== | ==About this Structure== | ||
| - | 1DTT 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 FTC as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1DTT 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=FTC:'>FTC</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DTT OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Balzarini, J.]] | [[Category: Balzarini, J.]] | ||
| - | [[Category: Bird, L | + | [[Category: Bird, L E.]] |
[[Category: Diprose, J.]] | [[Category: Diprose, J.]] | ||
| - | [[Category: Esnouf, R | + | [[Category: Esnouf, R M.]] |
[[Category: Ikemizu, S.]] | [[Category: Ikemizu, S.]] | ||
[[Category: Milton, J.]] | [[Category: Milton, J.]] | ||
[[Category: Ren, J.]] | [[Category: Ren, J.]] | ||
[[Category: Slater, M.]] | [[Category: Slater, M.]] | ||
| - | [[Category: Stammers, D | + | [[Category: Stammers, D K.]] |
| - | [[Category: Stuart, D | + | [[Category: Stuart, D I.]] |
[[Category: Warren, J.]] | [[Category: Warren, J.]] | ||
[[Category: FTC]] | [[Category: FTC]] | ||
| Line 30: | Line 29: | ||
[[Category: non-nucleoside inhibitor]] | [[Category: non-nucleoside inhibitor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:20:21 2008'' |
Revision as of 10:20, 21 February 2008
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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 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
Page seeded by OCA on Thu Feb 21 12:20:21 2008
