Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening

J Med Chem. 2013 Apr 11;56(7):2738-46. doi: 10.1021/jm301271j. Epub 2013 Feb 20.


HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites (Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding) are inhibitory and provide opportunities for discovery of new anti-AIDS drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Allosteric Site
  • Base Sequence
  • Crystallography, X-Ray
  • DNA Primers
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism*
  • Models, Molecular
  • Protein Conformation


  • DNA Primers
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase

Associated data

  • PDB/4I7G
  • PDB/4ICL
  • PDB/4ID4
  • PDB/4IDK
  • PDB/4IFV
  • PDB/4IFY
  • PDB/4IG0
  • PDB/4IG3