X-ray crystallographic structure of a complex between a synthetic protease of human immunodeficiency virus 1 and a substrate-based hydroxyethylamine inhibitor

Proc Natl Acad Sci U S A. 1990 Nov;87(22):8805-9. doi: 10.1073/pnas.87.22.8805.

Abstract

The structure of a crystal complex of the chemically synthesized protease of human immunodeficiency virus 1 with a heptapeptide-derived inhibitor bound in the active site has been determined. The sequence of the inhibitor JG-365 is Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe; the Ki is 0.24 nM. The hydroxyethylamine moiety, in place of the normal scissile bond of the substrate, is believed to mimic a tetrahedral reaction intermediate. The structure of the complex has been refined to an R factor of 0.146 at 2.4-A resolution by using restrained least squares with rms deviations in bond lengths of 0.02 A and bond angles of 4. The bound inhibitor diastereomer has the S configuration at the hydroxyethylamine chiral carbon, and the hydroxyl group is positioned between the active site aspartate carboxyl groups within hydrogen bonding distance. Comparison of this structure with a reduced peptide bond inhibitor-protease complex indicates that these contacts confer the exceptional binding strength of JG-365.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography
  • Drug Design
  • HIV Protease Inhibitors*
  • Models, Molecular
  • Molecular Sequence Data
  • Oligopeptides / chemistry*
  • Protease Inhibitors / chemistry*
  • Protein Conformation
  • X-Ray Diffraction

Substances

  • HIV Protease Inhibitors
  • Oligopeptides
  • Protease Inhibitors
  • JG 365

Associated data

  • PDB/UNKNOWN