1bqm
From Proteopedia
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|SITE= | |SITE= | ||
|LIGAND= <scene name='pdbligand=HBY:(S)-4-ISOPROPOXYCARBONYL-6-METHOXY-3-METHYLTHIOMETHYL-3,4-DIHYDROQUINOXALIN-2(1H)-THIONE'>HBY</scene> | |LIGAND= <scene name='pdbligand=HBY:(S)-4-ISOPROPOXYCARBONYL-6-METHOXY-3-METHYLTHIOMETHYL-3,4-DIHYDROQUINOXALIN-2(1H)-THIONE'>HBY</scene> | ||
| - | |ACTIVITY= [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] | + | |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> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1bqm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1bqm OCA], [http://www.ebi.ac.uk/pdbsum/1bqm PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1bqm RCSB]</span> | ||
}} | }} | ||
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[[Category: Ding, J.]] | [[Category: Ding, J.]] | ||
[[Category: Hsiou, Y.]] | [[Category: Hsiou, Y.]] | ||
| - | [[Category: HBY]] | ||
[[Category: aid]] | [[Category: aid]] | ||
[[Category: drug-resistant mutant]] | [[Category: drug-resistant mutant]] | ||
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[[Category: rna-directed dna polymerase]] | [[Category: rna-directed dna polymerase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:06:20 2008'' |
Revision as of 16:06, 30 March 2008
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| , resolution 3.1Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Activity: | RNA-directed DNA polymerase, with EC number 2.7.7.49 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HIV-1 RT/HBY 097
Overview
The second generation Hoechst-Bayer non-nucleoside inhibitor, HBY 097 (S-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroqui noxalin-2(1H)-thione), is an extremely potent inhibitor of HIV-1 reverse transcriptase (RT) and of HIV-1 infection in cell culture. HBY 097 selects for unusual drug-resistance mutations in HIV-1 RT (e.g. Gly190Glu) when compared with other non-nucleoside RT inhibitors (NNRTIs), such as nevirapine, alpha-APA and TIBO. We have determined the structure of HBY 097 complexed with wild-type HIV-1 RT at 3.1 A resolution. The HIV-1 RT/HBY 097 structure reveals an overall inhibitor geometry and binding mode differing significantly from RT/NNRTI structures reported earlier, in that HBY 097 does not adopt the usual butterfly-like shape. We have determined the structure of the Tyr188Leu HIV-1 RT drug-resistant mutant in complex with HBY 097 at 3.3 A resolution. HBY 097 binds to the mutant RT in a manner similar to that seen in the wild-type RT/HBY 097 complex, although there are some repositioning and conformational alterations of the inhibitor. Conformational changes of the structural elements forming the inhibitor-binding pocket, including the orientation of some side-chains, are observed. Reduction in the size of the 188 side-chain and repositioning of the Phe227 side-chain increases the volume of the binding cavity in the Tyr188Leu HIV-1 RT/HBY 097 complex. Loss of important protein-inhibitor interactions may account for the reduced potency of HBY 097 against the Tyr188Leu HIV-1 RT mutant. The loss of binding energy may be partially offset by additional contacts resulting from conformational changes of the inhibitor and nearby amino acid residues. This would suggest that inhibitor flexibility can help to minimize drug resistance.
About this Structure
1BQM is a Protein complex structure of sequences from Human immunodeficiency virus 1 and Human immunodeficiency virus type 1 (isolate 12). Full crystallographic information is available from OCA.
Reference
Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance., Hsiou Y, Das K, Ding J, Clark AD Jr, Kleim JP, Rosner M, Winkler I, Riess G, Hughes SH, Arnold E, J Mol Biol. 1998 Nov 27;284(2):313-23. PMID:9813120
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