1fko: Difference between revisions
New page: left|200px<br /> <applet load="1fko" size="450" color="white" frame="true" align="right" spinBox="true" caption="1fko, resolution 2.9Å" /> '''CRYSTAL STRUCTURE OF... |
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[[Image:1fko.gif|left|200px]]<br /> | [[Image:1fko.gif|left|200px]]<br /><applet load="1fko" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="1fko, resolution 2.9Å" /> | caption="1fko, resolution 2.9Å" /> | ||
'''CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)'''<br /> | '''CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)'''<br /> | ||
==Overview== | ==Overview== | ||
BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of | BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency. | ||
==About this Structure== | ==About this Structure== | ||
1FKO 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 EFZ as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] Full crystallographic information is available from [http:// | 1FKO 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=EFZ:'>EFZ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FKO OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Milton, J.]] | [[Category: Milton, J.]] | ||
[[Category: Ren, J.]] | [[Category: Ren, J.]] | ||
[[Category: Short, S | [[Category: Short, S A.]] | ||
[[Category: Stammers, D | [[Category: Stammers, D K.]] | ||
[[Category: Stuart, D | [[Category: Stuart, D I.]] | ||
[[Category: Weaver, K | [[Category: Weaver, K L.]] | ||
[[Category: EFZ]] | [[Category: EFZ]] | ||
[[Category: aids]] | [[Category: aids]] | ||
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[[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 12:39:40 2008'' | ||
Revision as of 13:39, 21 February 2008
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CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)
OverviewOverview
BACKGROUND: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant. RESULTS: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine. CONCLUSIONS: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.
About this StructureAbout this Structure
1FKO 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
Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase., Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK, Structure. 2000 Oct 15;8(10):1089-94. PMID:11080630
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