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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
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Allosteric suppression of HIV-1 reverse transcriptase structural dynamics upon inhibitor binding.

James M Seckler1, Mary D Barkley, Patrick L Wintrode

  • 1Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, USA.

Biophysical Journal
|December 31, 2010
PubMed
Summary

Efavirenz, an anti-AIDS drug, alters the flexibility of the reverse transcriptase (RT) enzyme beyond its direct binding site. This drug impacts enzyme dynamics, revealing potential new targets for HIV therapy.

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Area of Science:

  • Structural biology
  • Virology
  • Pharmacology

Background:

  • Efavirenz is a key component in anti-AIDS therapies, acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI).
  • NNRTIs bind to a hydrophobic pocket on the reverse transcriptase (RT) enzyme, approximately 10 Å from the active site.

Purpose of the Study:

  • To investigate the allosteric effects of efavirenz binding on the structural dynamics of the reverse transcriptase (RT) enzyme.
  • To identify regions of structural stabilization and destabilization induced by efavirenz.
  • To explore potential new drug targets based on efavirenz-induced allosteric changes.

Main Methods:

  • Hydrogen exchange mass spectrometry (HXMS) was employed to monitor changes in molecular flexibility.
  • 47 peptic fragments of the RT enzyme were analyzed for altered H/D exchange rates in the presence of efavirenz.

Main Results:

  • Efavirenz binding significantly reduced molecular flexibility in multiple regions of the RT heterodimer, extending over 60 Å from the binding site.
  • The cooperative unfolding of a β-sheet in the NNRTI binding pocket was suppressed by efavirenz.
  • HXMS identified extensive allosteric coupling, including four regions of stabilization and one of destabilization.

Conclusions:

  • Efavirenz binding induces widespread allosteric changes in RT structural dynamics, affecting various subdomains and the RNase H domain.
  • These allosteric effects propagate throughout the enzyme, influencing both p66 and p51 subunits.
  • The identified allosteric regions represent potential novel targets for future anti-HIV drug development.