Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase

Structure. 2000 Oct 15;8(10):1089-94. doi: 10.1016/s0969-2126(00)00513-x.


Background: Efavirenz is a second-generation non-nucleoside inhibitor of HIV-1 reverse transcriptase (RT) that has recently been approved for use against HIV-1 infection. Compared with first-generation drugs such as nevirapine, efavirenz shows greater resilience to drug resistance mutations within HIV-1 RT. In order to understand the basis for this resilience at the molecular level and to help the design of further-improved anti-AIDS drugs, we have determined crystal structures of efavirenz and nevirapine with wild-type RT and the clinically important K103N mutant.

Results: The relatively compact efavirenz molecule binds, as expected, within the non-nucleoside inhibitor binding pocket of RT. There are significant rearrangements of the drug binding site within the mutant RT compared with the wild-type enzyme. These changes, which lead to the repositioning of the inhibitor, are not seen in the interaction with the first-generation drug nevirapine.

Conclusions: The repositioning of efavirenz within the drug binding pocket of the mutant RT, together with conformational rearrangements in the protein, could represent a general mechanism whereby certain second-generation non-nucleoside inhibitors are able to reduce the effect of drug-resistance mutations on binding potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes
  • Amino Acid Substitution / genetics
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology
  • Benzoxazines
  • Binding Sites
  • Crystallography, X-Ray
  • Cyclopropanes
  • Drug Resistance, Microbial / genetics
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • HIV-1 / genetics
  • Humans
  • Models, Molecular
  • Mutation / genetics*
  • Nevirapine / chemistry
  • Nevirapine / metabolism
  • Nevirapine / pharmacology
  • Oxazines / chemistry*
  • Oxazines / metabolism
  • Oxazines / pharmacology*
  • Protein Binding
  • Protein Conformation
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship


  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Oxazines
  • Reverse Transcriptase Inhibitors
  • Nevirapine
  • HIV Reverse Transcriptase
  • efavirenz

Associated data

  • PDB/1FK9
  • PDB/1FKO
  • PDB/1FKP