1jkh: Difference between revisions

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[[Image:1jkh.gif|left|200px]]
[[Image:1jkh.gif|left|200px]]


{{Structure
<!--
|PDB= 1jkh |SIZE=350|CAPTION= <scene name='initialview01'>1jkh</scene>, resolution 2.50&Aring;
The line below this paragraph, containing "STRUCTURE_1jkh", creates the "Structure Box" on the page.
|SITE=
You may change the PDB parameter (which sets the PDB file loaded into the applet)
|LIGAND= <scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene>, <scene name='pdbligand=EFZ:(-)-6-CHLORO-4-CYCLOPROPYLETHYNYL-4-TRIFLUOROMETHYL-1,4-DIHYDRO-2H-3,1-BENZOXAZIN-2-ONE'>EFZ</scene>
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
|ACTIVITY= <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>
or leave the SCENE parameter empty for the default display.
|GENE= POL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id= Human immunodeficiency virus type 1 (isolate HXB2)])
-->
|DOMAIN=
{{STRUCTURE_1jkh| PDB=1jkh  | SCENE= }}  
|RELATEDENTRY=[[1vrt|1VRT]], [[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]], [[1fkp|1FKP]], [[1jlc|1JLC]], [[1jla|1JLA]], [[1jlb|1JLB]], [[1jlf|1JLF]], [[1jle|1JLE]], [[1jlq|1JLQ]], [[1jlg|1JLG]]
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1jkh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jkh OCA], [http://www.ebi.ac.uk/pdbsum/1jkh PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1jkh RCSB]</span>
}}


'''CRYSTAL STRUCTURE OF Y181C MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)'''
'''CRYSTAL STRUCTURE OF Y181C MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)'''
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==Reference==
==Reference==
Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors., Ren J, Nichols C, Bird L, Chamberlain P, Weaver K, Short S, Stuart DI, Stammers DK, J Mol Biol. 2001 Sep 28;312(4):795-805. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11575933 11575933]
Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors., Ren J, Nichols C, Bird L, Chamberlain P, Weaver K, Short S, Stuart DI, Stammers DK, J Mol Biol. 2001 Sep 28;312(4):795-805. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11575933 11575933]
[[Category: Human immunodeficiency virus type 1 (isolate hxb2)]]
[[Category: Protein complex]]
[[Category: Protein complex]]
[[Category: RNA-directed DNA polymerase]]
[[Category: RNA-directed DNA polymerase]]
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[[Category: Stuart, D I.]]
[[Category: Stuart, D I.]]
[[Category: Weaver, K.]]
[[Category: Weaver, K.]]
[[Category: aid]]
[[Category: Aid]]
[[Category: dmp-266]]
[[Category: Dmp-266]]
[[Category: drug design]]
[[Category: Drug design]]
[[Category: drug resistance mutation]]
[[Category: Drug resistance mutation]]
[[Category: efavirenz]]
[[Category: Efavirenz]]
[[Category: hiv-1 reverse transcriptase]]
[[Category: Hiv-1 reverse transcriptase]]
[[Category: non-nucleoside inhibitor]]
[[Category: Non-nucleoside inhibitor]]
 
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 21:34:57 2008''

Revision as of 21:20, 2 May 2008

File:1jkh.gif

Template:STRUCTURE 1jkh

CRYSTAL STRUCTURE OF Y181C MUTANT HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DMP-266(EFAVIRENZ)


OverviewOverview

Mutations at either Tyr181 or Tyr188 within HIV-1 reverse transcriptase (RT) give high level resistance to many first generation non-nucleoside inhibitors (NNRTIs) such as the anti-AIDS drug nevirapine. By comparison second generation inhibitors, for instance the drug efavirenz, show much greater resilience to these mutations. In order to understand the structural basis for these differences we have determined a series of seven crystal structures of mutant RTs in complexes with first and second generation NNRTIs as well as one example of an unliganded mutant RT. These are Tyr181Cys RT (TNK-651) to 2.4 A, Tyr181Cys RT (efavirenz) to 2.6 A, Tyr181Cys RT (nevirapine) to 3.0 A, Tyr181Cys RT (PETT-2) to 3.0 A, Tyr188Cys RT (nevirapine) to 2.6 A, Tyr188Cys RT (UC-781) to 2.6 A and Tyr188Cys RT (unliganded) to 2.8 A resolution. In the two previously published structures of HIV-1 reverse transcriptase with mutations at 181 or 188 no side-chain electron density was observed within the p66 subunit (which contains the inhibitor binding pocket) for the mutated residues. In contrast the mutated side-chains can be seen in the NNRTI pocket for all seven structures reported here, eliminating the possibility that disordering contributes to the mechanism of resistance. In the case of the second generation compounds efavirenz with Tyr181Cys RT and UC-781 with Tyr188Cys RT there are only small rearrangements of either inhibitor within the binding site compared to wild-type RT and also for the first generation compounds TNK-651, PETT-2 and nevirapine with Tyr181Cys RT. For nevirapine with the Tyr188Cys RT there is however a more substantial movement of the drug molecule. We conclude that protein conformational changes and rearrangements of drug molecules within the mutated sites are not general features of these particular inhibitor/mutant combinations. The main contribution to drug resistance for Tyr181Cys and Tyr188Cys RT mutations is the loss of aromatic ring stacking interactions for first generation compounds, providing a simple explanation for the resilience of second generation NNRTIs, as such interactions make much less significant contribution to their binding.

About this StructureAbout this Structure

1JKH is a Protein complex structure of sequences from Human immunodeficiency virus type 1 (isolate hxb2). Full crystallographic information is available from OCA.

ReferenceReference

Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors., Ren J, Nichols C, Bird L, Chamberlain P, Weaver K, Short S, Stuart DI, Stammers DK, J Mol Biol. 2001 Sep 28;312(4):795-805. PMID:11575933 Page seeded by OCA on Fri May 2 21:20:00 2008

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