Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain

Acta Crystallogr D Biol Crystallogr. 2001 Apr;57(Pt 4):536-44. doi: 10.1107/s0907444901001652.


Integration of the reverse-transcribed HIV cDNA into the host DNA is a required step in viral replication. The virus-encoded integrase protein catalyzes the initial DNA breaking and joining reactions that mediate cDNA integration. Here, the identification by X-ray crystallography of a small-molecule binding site on the integrase catalytic domain is reported. The small-molecule family studied consists of a core of arsenic or phosphorus surrounded by four aromatic groups. Two arsenic derivatives were visualized bound to integrase. In each case, two molecules bound at symmetry-related sites on the catalytic domain dimer interface. The first compound studied, tetraphenyl arsonium, did not inhibit integrase. However, a synthetic compound substituting a catechol for one of the phenyl rings, dihydroxyphenyltriphenylarsonium, bound to the same site and did inhibit the enzyme. Changes in the vicinity of the catalytic site were seen with the inhibitory compound only, potentially explaining its mechanism of action. Further substituting phosphonium for arsonium yielded a compound with an IC(50) in the low micromolar range. These findings may be useful in designing new inhibitors of integrase, which is at present the only one of the three HIV enzymes for which clinically useful inhibitors are not available.

Publication types

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

MeSH terms

  • Amino Acid Substitution / genetics
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology
  • Base Sequence
  • Binding Sites
  • Catalytic Domain*
  • Crystallography, X-Ray
  • Dimerization
  • Electrophoresis, Polyacrylamide Gel
  • HIV Integrase / chemistry*
  • HIV Integrase / genetics
  • HIV Integrase / metabolism*
  • HIV Integrase Inhibitors / chemistry
  • HIV Integrase Inhibitors / metabolism*
  • HIV Integrase Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • HIV-1 / genetics
  • Models, Molecular
  • Protein Structure, Quaternary
  • Static Electricity


  • Anti-HIV Agents
  • HIV Integrase Inhibitors
  • HIV Integrase

Associated data

  • PDB/1HYV
  • PDB/1HYZ