1HYV

HIV INTEGRASE CORE DOMAIN COMPLEXED WITH TETRAPHENYL ARSONIUM

Summary for 1HYV

• Entry DOI: 10.2210/pdb1hyv/pdb
• Related: 1HYZ
• Descriptor: INTEGRASE, SULFATE ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: dna integration, transferase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 18949.58

Authors

Molteni, V.,Greenwald, J.,Rhodes, D.,Hwang, Y.,Kwiatkowski, W.,Bushman, F.D.,Siegel, J.S.,Choe, S. (deposition date: 2001-01-22, release date: 2001-04-04, Last modification date: 2021-10-27)

Primary citation

Molteni, V.,Greenwald, J.,Rhodes, D.,Hwang, Y.,Kwiatkowski, W.,Bushman, F.D.,Siegel, J.S.,Choe, S.
Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain.
Acta Crystallogr.,Sect.D, 57:536-544, 2001

PubMed Abstract: 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.

PubMed: 11264582
DOI: 10.1107/S0907444901001652

Experimental method

X-RAY DIFFRACTION (1.7 Å)