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Structural insights into mechanisms of non-nucleoside drug resistance for HIV-1 reverse transcriptases mutated at codons 101 or 138.

Ren J, Nichols CE, Stamp A, Chamberlain PP, Ferris R, Weaver KL, Short SA, Stammers DK
FEBS J 273 3850-60 (2006)
Related entries: 2hny, 2hnz

Cited: 38 times
EuropePMC logo PMID: 16911530

Abstract

Lys101Glu is a drug resistance mutation in reverse transcriptase clinically observed in HIV-1 from infected patients treated with the non-nucleoside inhibitor (NNRTI) drugs nevirapine and efavirenz. In contrast to many NNRTI resistance mutations, Lys101(p66 subunit) is positioned at the surface of the NNRTI pocket where it interacts across the reverse transcriptase (RT) subunit interface with Glu138(p51 subunit). However, nevirapine contacts Lys101 and Glu138 only indirectly, via water molecules, thus the structural basis of drug resistance induced by Lys101Glu is unclear. We have determined crystal structures of RT(Glu138Lys) and RT(Lys101Glu) in complexes with nevirapine to 2.5 A, allowing the determination of water structure within the NNRTI-binding pocket, essential for an understanding of nevirapine binding. Both RT(Glu138Lys) and RT(Lys101Glu) have remarkably similar protein conformations to wild-type RT, except for significant movement of the mutated side-chains away from the NNRTI pocket induced by charge inversion. There are also small shifts in the position of nevirapine for both mutant structures which may influence ring stacking interactions with Tyr181. However, the reduction in hydrogen bonds in the drug-water-side-chain network resulting from the mutated side-chain movement appears to be the most significant contribution to nevirapine resistance for RT(Lys101Glu). The movement of Glu101 away from the NNRTI pocket can also explain the resistance of RT(Lys101Glu) to efavirenz but in this case is due to a loss of side-chain contacts with the drug. RT(Lys101Glu) is thus a distinctive NNRTI resistance mutant in that it can give rise to both direct and indirect mechanisms of drug resistance, which are inhibitor-dependent.

Reviews - 2hnd mentioned but not cited (1)

  1. Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review. Tarasova O, Poroikov V, Veselovsky A. Molecules 23 E1233 (2018)

Articles - 2hnd mentioned but not cited (6)

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  6. Small Conformational Changes Underlie Evolution of Resistance to NNRTI in HIV Reverse Transcriptase. Srivastava A, Birari V, Sinha S. Biophys J 118 2489-2501 (2020)


Reviews citing this publication (5)

  1. Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Ren J, Stammers DK. Virus Res 134 157-170 (2008)
  2. HIV-1 reverse transcriptase and antiviral drug resistance. Part 2. Das K, Arnold E. Curr Opin Virol 3 119-128 (2013)
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  3. Crystal structure of tert-butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in complex with HIV-1 reverse transcriptase (RT) redefines the elastic limits of the non-nucleoside inhibitor-binding pocket. Das K, Bauman JD, Rim AS, Dharia C, Clark AD, Camarasa MJ, Balzarini J, Arnold E. J Med Chem 54 2727-2737 (2011)
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  5. Bridge water mediates nevirapine binding to wild type and Y181C HIV-1 reverse transcriptase--evidence from molecular dynamics simulations and MM-PBSA calculations. Treesuwan W, Hannongbua S. J Mol Graph Model 27 921-929 (2009)
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  11. Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase. Melody K, McBeth S, Kline C, Kashuba AD, Mellors JW, Ambrose Z. Antimicrob Agents Chemother 59 7762-7770 (2015)
  12. Molecular docking studies of marine diterpenes as inhibitors of wild-type and mutants HIV-1 reverse transcriptase. Miceli LA, Teixeira VL, Castro HC, Rodrigues CR, Mello JF, Albuquerque MG, Cabral LM, de Brito MA, de Souza AM. Mar Drugs 11 4127-4143 (2013)
  13. Role of the K101E substitution in HIV-1 reverse transcriptase in resistance to rilpivirine and other nonnucleoside reverse transcriptase inhibitors. Xu HT, Colby-Germinario SP, Huang W, Oliveira M, Han Y, Quan Y, Petropoulos CJ, Wainberg MA. Antimicrob Agents Chemother 57 5649-5657 (2013)
  14. Additional HIV-1 mutation patterns associated with reduced phenotypic susceptibility to etravirine in clinical samples. Kagan RM, Sista P, Pattery T, Bacheler L, Schwab DA. AIDS 23 1602-1605 (2009)
  15. Synthesis and evaluation of novel 3-(3,5-dimethylbenzyl)uracil analogs as potential anti-HIV-1 agents. Sakakibara N, Hamasaki T, Baba M, Demizu Y, Kurihara M, Irie K, Iwai M, Asada E, Kato Y, Maruyama T. Bioorg Med Chem 21 5900-5906 (2013)
  16. A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase. Mislak AC, Frey KM, Bollini M, Jorgensen WL, Anderson KS. Biochim Biophys Acta 1840 2203-2211 (2014)
  17. Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study. Ashford MW, Xu C, Molloy JJ, Carpenter-Warren C, Slawin AMZ, Leach AG, Watson AJB, Watson AJB. Chemistry 26 12249-12255 (2020)
  18. Antiretroviral resistance in HIV-1 patients at a tertiary medical institute in Saudi Arabia: a retrospective study and analysis. Al-Mozaini M, Alrahbeni T, Al-Mograbi R, Alrajhi A. BMC Infect Dis 18 425 (2018)
  19. Design, synthesis, and anti-HIV-1 activity of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives. Sakakibara N, Baba M, Okamoto M, Toyama M, Demizu Y, Misawa T, Kurihara M, Irie K, Kato Y, Maruyama T. Antivir Chem Chemother 24 3-18 (2015)
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  22. Residue-ligand interaction energy (ReLIE) on a receptor-dependent 3D-QSAR analysis of S- and NH-DABOs as non-nucleoside reverse transcriptase inhibitors. de Brito MA, Rodrigues CR, Cirino JJ, Araújo JQ, Honório T, Cabral LM, de Alencastro RB, Castro HC, Albuquerque MG. Molecules 17 7666-7694 (2012)
  23. Biophysical Insights into the Inhibitory Mechanism of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors. Schauer G, Leuba S, Sluis-Cremer N. Biomolecules 3 889-904 (2013)
  24. Cryo-EM structures of wild-type and E138K/M184I mutant HIV-1 RT/DNA complexed with inhibitors doravirine and rilpivirine. Singh AK, De Wijngaert B, Bijnens M, Uyttersprot K, Nguyen H, Martinez SE, Schols D, Herdewijn P, Pannecouque C, Arnold E, Das K. Proc Natl Acad Sci U S A 119 e2203660119 (2022)
  25. Structural Basis of 2-Phenylamino-4-phenoxyquinoline Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors. Makarasen A, Patnin S, Vijitphan P, Reukngam N, Khlaychan P, Kuno M, Intachote P, Saimanee B, Sengsai S, Techasakul S. Molecules 27 461 (2022)
  26. Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase. Wang Y, Wang A, Wang J, Wu X, Sun Y, Wu Y. Molecules 27 7348 (2022)


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