2ze2

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{{STRUCTURE_2ze2| PDB=2ze2 | SCENE= }}
{{STRUCTURE_2ze2| PDB=2ze2 | SCENE= }}
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'''Crystal structure of L100I/K103N mutant HIV-1 reverse transcriptase (RT) in complex with TMC278 (rilpivirine), a non-nucleoside RT inhibitor'''
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===Crystal structure of L100I/K103N mutant HIV-1 reverse transcriptase (RT) in complex with TMC278 (rilpivirine), a non-nucleoside RT inhibitor===
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==Overview==
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TMC278 is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that is highly effective in treating wild-type and drug-resistant HIV-1 infections in clinical trials at relatively low doses ( approximately 25-75 mg/day). We have determined the structure of wild-type HIV-1 RT complexed with TMC278 at 1.8 A resolution, using an RT crystal form engineered by systematic RT mutagenesis. This high-resolution structure reveals that the cyanovinyl group of TMC278 is positioned in a hydrophobic tunnel connecting the NNRTI-binding pocket to the nucleic acid-binding cleft. The crystal structures of TMC278 in complexes with the double mutant K103N/Y181C (2.1 A) and L100I/K103N HIV-1 RTs (2.9 A) demonstrated that TMC278 adapts to bind mutant RTs. In the K103N/Y181C RT/TMC278 structure, loss of the aromatic ring interaction caused by the Y181C mutation is counterbalanced by interactions between the cyanovinyl group of TMC278 and the aromatic side chain of Y183, which is facilitated by an approximately 1.5 A shift of the conserved Y(183)MDD motif. In the L100I/K103N RT/TMC278 structure, the binding mode of TMC278 is significantly altered so that the drug conforms to changes in the binding pocket primarily caused by the L100I mutation. The flexible binding pocket acts as a molecular "shrink wrap" that makes a shape complementary to the optimized TMC278 in wild-type and drug-resistant forms of HIV-1 RT. The crystal structures provide a better understanding of how the flexibility of an inhibitor can compensate for drug-resistance mutations.
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{{ABSTRACT_PUBMED_18230722}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations., Das K, Bauman JD, Clark AD Jr, Frenkel YV, Lewi PJ, Shatkin AJ, Hughes SH, Arnold E, Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1466-71. Epub 2008 Jan 29. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18230722 18230722]
High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations., Das K, Bauman JD, Clark AD Jr, Frenkel YV, Lewi PJ, Shatkin AJ, Hughes SH, Arnold E, Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1466-71. Epub 2008 Jan 29. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18230722 18230722]
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Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097., Das K, Sarafianos SG, Clark AD Jr, Boyer PL, Hughes SH, Arnold E, J Mol Biol. 2007 Jan 5;365(1):77-89. Epub 2006 Sep 15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17056061 17056061]
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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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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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The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance., Hsiou Y, Ding J, Das K, Clark AD Jr, Boyer PL, Lewi P, Janssen PA, Kleim JP, Rosner M, Hughes SH, Arnold E, J Mol Biol. 2001 Jun 1;309(2):437-45. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11371163 11371163]
[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: Rna-directed dna polymerase]]
[[Category: Rna-directed dna polymerase]]
[[Category: Transferase]]
[[Category: Transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 20:10:06 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 05:36:29 2008''

Revision as of 02:36, 29 July 2008

Image:2ze2.png

Template:STRUCTURE 2ze2

Crystal structure of L100I/K103N mutant HIV-1 reverse transcriptase (RT) in complex with TMC278 (rilpivirine), a non-nucleoside RT inhibitor

Template:ABSTRACT PUBMED 18230722

About this Structure

2ZE2 is a Protein complex structure of sequences from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

Reference

High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations., Das K, Bauman JD, Clark AD Jr, Frenkel YV, Lewi PJ, Shatkin AJ, Hughes SH, Arnold E, Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1466-71. Epub 2008 Jan 29. PMID:18230722

Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097., Das K, Sarafianos SG, Clark AD Jr, Boyer PL, Hughes SH, Arnold E, J Mol Biol. 2007 Jan 5;365(1):77-89. Epub 2006 Sep 15. PMID:17056061

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

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

The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance., Hsiou Y, Ding J, Das K, Clark AD Jr, Boyer PL, Lewi P, Janssen PA, Kleim JP, Rosner M, Hughes SH, Arnold E, J Mol Biol. 2001 Jun 1;309(2):437-45. PMID:11371163

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