1rt3: Difference between revisions

Revision as of 15:54, 21 February 2008

AZT DRUG RESISTANT HIV-1 REVERSE TRANSCRIPTASE COMPLEXED WITH 1051U91

OverviewOverview

HIV reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. Many of these drugs [e.g., 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI)] are analogues of the nucleoside substrates used by the HIV RT. One of the main problems in anti-HIV therapy is the selection of a mutant virus with reduced drug sensitivity. Drug resistance in HIV is generated for nucleoside analogue inhibitors by mutations in HIV RT. However, most of these mutations are situated some distance from the polymerase active site, giving rise to questions concerning the mechanism of resistance. To understand the possible structural bases for this, the crystal structures of AZT- and ddI-resistant RTs have been determined. For the ddI-resistant RT with a mutation at residue 74, no significant conformational changes were observed for the p66 subunit. In contrast, for the AZT-resistant RT (RTMC) bearing four mutations, two of these (at 215 and 219) give rise to a conformational change that propagates to the active site aspartate residues. Thus, these drug resistance mutations produce an effect at the RT polymerase site mediated simply by the protein. It is likely that such long-range effects could represent a common mechanism for generating drug resistance in other systems.

About this StructureAbout this Structure

1RT3 is a Protein complex structure of sequences from Human immunodeficiency virus 1 with as ligand. Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.

ReferenceReference

3'-Azido-3'-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes., Ren J, Esnouf RM, Hopkins AL, Jones EY, Kirby I, Keeling J, Ross CK, Larder BA, Stuart DI, Stammers DK, Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9518-23. PMID:9689112

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 ==Overview==
-HIV reverse transcriptase (RT) is one of the main targets for the action, of anti-AIDS drugs. Many of these drugs [e.g., 3'-azido-3'-deoxythymidine, (AZT) and 2',3'-dideoxyinosine (ddI)] are analogues of the nucleoside, substrates used by the HIV RT. One of the main problems in anti-HIV, therapy is the selection of a mutant virus with reduced drug sensitivity., Drug resistance in HIV is generated for nucleoside analogue inhibitors by, mutations in HIV RT. However, most of these mutations are situated some, distance from the polymerase active site, giving rise to questions, concerning the mechanism of resistance. To understand the possible, structural bases for this, the crystal structures of AZT- and, ddI-resistant RTs have been determined. For the ddI-resistant RT with a, mutation at residue 74, no significant conformational changes were, observed for the p66 subunit. In contrast, for the AZT-resistant RT (RTMC), bearing four mutations, two of these (at 215 and 219) give rise to a, conformational change that propagates to the active site aspartate, residues. Thus, these drug resistance mutations produce an effect at the, RT polymerase site mediated simply by the protein. It is likely that such, long-range effects could represent a common mechanism for generating drug, resistance in other systems.
+HIV reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. Many of these drugs [e.g., 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI)] are analogues of the nucleoside substrates used by the HIV RT. One of the main problems in anti-HIV therapy is the selection of a mutant virus with reduced drug sensitivity. Drug resistance in HIV is generated for nucleoside analogue inhibitors by mutations in HIV RT. However, most of these mutations are situated some distance from the polymerase active site, giving rise to questions concerning the mechanism of resistance. To understand the possible structural bases for this, the crystal structures of AZT- and ddI-resistant RTs have been determined. For the ddI-resistant RT with a mutation at residue 74, no significant conformational changes were observed for the p66 subunit. In contrast, for the AZT-resistant RT (RTMC) bearing four mutations, two of these (at 215 and 219) give rise to a conformational change that propagates to the active site aspartate residues. Thus, these drug resistance mutations produce an effect at the RT polymerase site mediated simply by the protein. It is likely that such long-range effects could represent a common mechanism for generating drug resistance in other systems.
 ==About this Structure==
@@ Line 15: / Line 15: @@
 [[Category: RNA-directed DNA polymerase]]
 [[Category: Ren, J.]]
-[[Category: Stammers, D.K.]]
+[[Category: Stammers, D K.]]
-[[Category: Stuart, D.I.]]
+[[Category: Stuart, D I.]]
 [[Category: U05]]
 [[Category: aids]]
@@ Line 24: / Line 24: @@
 [[Category: nucleotidyltransferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:49:36 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:54:12 2008''