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[[Image: | ==CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH NEVIRAPINE== | ||
<StructureSection load='1fkp' size='340' side='right' caption='[[1fkp]], [[Resolution|resolution]] 2.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1fkp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FKP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1FKP FirstGlance]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NVP:11-CYCLOPROPYL-5,11-DIHYDRO-4-METHYL-6H-DIPYRIDO[3,2-B 2,3-E][1,4]DIAZEPIN-6-ONE'>NVP</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene></td></tr> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1rtv|1rtv]], [[1rth|1rth]], [[1vru|1vru]], [[1rti|1rti]], [[1rtj|1rtj]], [[1rev|1rev]], [[1rt1|1rt1]], [[1rt2|1rt2]], [[1klm|1klm]], [[1rt3|1rt3]], [[1rt4|1rt4]], [[1rt5|1rt5]], [[1rt6|1rt6]], [[1rt7|1rt7]], [[1c0t|1c0t]], [[1c0u|1c0u]], [[1c1b|1c1b]], [[1c1c|1c1c]], [[1dtq|1dtq]], [[1dtt|1dtt]], [[1ep4|1ep4]], [[1fk9|1fk9]], [[1fko|1fko]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1fkp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fkp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1fkp RCSB], [http://www.ebi.ac.uk/pdbsum/1fkp PDBsum]</span></td></tr> | |||
<table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fk/1fkp_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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<ref>PMID:11080630</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Reverse transcriptase|Reverse transcriptase]] | *[[Reverse transcriptase|Reverse transcriptase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: RNA-directed DNA polymerase]] | [[Category: RNA-directed DNA polymerase]] | ||
Revision as of 11:47, 28 September 2014
CRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH NEVIRAPINECRYSTAL STRUCTURE OF NNRTI RESISTANT K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH NEVIRAPINE
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBACKGROUND: 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences |
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