1dtt: Difference between revisions

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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="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1dtt, resolution 3.0Å" />

'''CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-2 (PETT130A94)'''<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==

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://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1DTT OCA].

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==

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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: FTC]]

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[[Category: non-nucleoside inhibitor]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on Thu ~~Nov 8 13~~:59:~~10 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:20:21 2008''

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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="450" color="white" frame="true" align="right" spinBox="true"
 caption="1dtt, resolution 3.0&Aring;" />
 '''CRYSTAL STRUCTURE OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH PETT-2 (PETT130A94)'''<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==
-DTT 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1DTT OCA].
+DTT 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==
@@ Line 15: / Line 14: @@
 [[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: FTC]]
@@ Line 30: / Line 29: @@
 [[Category: non-nucleoside inhibitor]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov  8 13:59:10 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:20:21 2008''