1sv5

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{{STRUCTURE_1sv5| PDB=1sv5 | SCENE= }}
{{STRUCTURE_1sv5| PDB=1sv5 | SCENE= }}
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'''CRYSTAL STRUCTURE OF K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE (RT) IN COMPLEX WITH JANSSEN-R165335'''
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===CRYSTAL STRUCTURE OF K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE (RT) IN COMPLEX WITH JANSSEN-R165335===
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==Overview==
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Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naive patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1). DAPY analogues can bind in at least two conformationally distinct modes; (2). within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3). the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets.
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{{ABSTRACT_PUBMED_15115397}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants., Das K, Clark AD Jr, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Bethune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E, J Med Chem. 2004 May 6;47(10):2550-60. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15115397 15115397]
Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants., Das K, Clark AD Jr, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Bethune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E, J Med Chem. 2004 May 6;47(10):2550-60. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15115397 15115397]
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Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors., Ding J, Das K, Moereels H, Koymans L, Andries K, Janssen PA, Hughes SH, Arnold E, Nat Struct Biol. 1995 May;2(5):407-15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7545077 7545077]
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Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor alpha-APA R 95845 at 2.8 A resolution., Ding J, Das K, Tantillo C, Zhang W, Clark AD Jr, Jessen S, Lu X, Hsiou Y, Jacobo-Molina A, Andries K, et al., Structure. 1995 Apr 15;3(4):365-79. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7542140 7542140]
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Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant., Das K, Ding J, Hsiou Y, Clark AD Jr, Moereels H, Koymans L, Andries K, Pauwels R, Janssen PA, Boyer PL, Clark P, Smith RH Jr, Kroeger Smith MB, Michejda CJ, Hughes SH, Arnold E, J Mol Biol. 1996 Dec 20;264(5):1085-100. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9000632 9000632]
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Structure and functional implications of the polymerase active site region in a complex of HIV-1 RT with a double-stranded DNA template-primer and an antibody Fab fragment at 2.8 A resolution., Ding J, Das K, Hsiou Y, Sarafianos SG, Clark AD Jr, Jacobo-Molina A, Tantillo C, Hughes SH, Arnold E, J Mol Biol. 1998 Dec 11;284(4):1095-111. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/9837729 9837729]
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Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues., Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Bethune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA, Bioorg Med Chem Lett. 2001 Sep 3;11(17):2235-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11527705 11527705]
[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: Reverse transcriptase]]
[[Category: Reverse transcriptase]]
[[Category: Rt]]
[[Category: Rt]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 04:33:43 2008''

Revision as of 01:33, 28 July 2008

Image:1sv5.png

Template:STRUCTURE 1sv5

CRYSTAL STRUCTURE OF K103N MUTANT HIV-1 REVERSE TRANSCRIPTASE (RT) IN COMPLEX WITH JANSSEN-R165335

Template:ABSTRACT PUBMED 15115397

About this Structure

1SV5 is a Protein complex structure of sequences from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

Reference

Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants., Das K, Clark AD Jr, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Bethune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E, J Med Chem. 2004 May 6;47(10):2550-60. PMID:15115397

Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors., Ding J, Das K, Moereels H, Koymans L, Andries K, Janssen PA, Hughes SH, Arnold E, Nat Struct Biol. 1995 May;2(5):407-15. PMID:7545077

Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor alpha-APA R 95845 at 2.8 A resolution., Ding J, Das K, Tantillo C, Zhang W, Clark AD Jr, Jessen S, Lu X, Hsiou Y, Jacobo-Molina A, Andries K, et al., Structure. 1995 Apr 15;3(4):365-79. PMID:7542140

Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant., Das K, Ding J, Hsiou Y, Clark AD Jr, Moereels H, Koymans L, Andries K, Pauwels R, Janssen PA, Boyer PL, Clark P, Smith RH Jr, Kroeger Smith MB, Michejda CJ, Hughes SH, Arnold E, J Mol Biol. 1996 Dec 20;264(5):1085-100. PMID:9000632

Structure and functional implications of the polymerase active site region in a complex of HIV-1 RT with a double-stranded DNA template-primer and an antibody Fab fragment at 2.8 A resolution., Ding J, Das K, Hsiou Y, Sarafianos SG, Clark AD Jr, Jacobo-Molina A, Tantillo C, Hughes SH, Arnold E, J Mol Biol. 1998 Dec 11;284(4):1095-111. PMID:9837729

Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues., Ludovici DW, De Corte BL, Kukla MJ, Ye H, Ho CY, Lichtenstein MA, Kavash RW, Andries K, de Bethune MP, Azijn H, Pauwels R, Lewi PJ, Heeres J, Koymans LM, de Jonge MR, Van Aken KJ, Daeyaert FF, Das K, Arnold E, Janssen PA, Bioorg Med Chem Lett. 2001 Sep 3;11(17):2235-9. PMID:11527705

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