Alternative native flap conformation revealed by 2.3 A resolution structure of SIV proteinase

J Mol Biol. 1994 May 27;239(1):97-103. doi: 10.1006/jmbi.1994.1353.

Abstract

A large conformational change is observed between HIV-1 proteinase in the ligand-free state and in complexes with transition-state inhibitors. Crystal structures of this enzyme have either the flaps open for the native or ligand-free enzyme or the flaps closed for peptidomimetic ligand-bound enzyme. We describe the structure of native recombinant SIV proteinase which like other retroviral proteinases crystallizes as a perfect 2-fold symmetric dimer but in a different crystal packing arrangement. In contrast to HIV-1 PR we show that SIV proteinase in the ligand-free state adopts the closed flaps conformation, demonstrating that ligand binding is not a prerequisite for the closed flaps conformation. The catalytic water was clearly observed between the two aspartates which were not perfectly co-planar, and in this structure the active site cleft is more restricted than for either inhibitor bound or ligand-free HIV-1 proteinase. Accommodation of two bulkier side-chains in the simian enzyme core has resulted in a more exposed N terminus than for HIV-1 PR which we predict could enhance autocatalytic cleavage at the N terminus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Aspartic Acid Endopeptidases / chemistry*
  • Aspartic Acid Endopeptidases / genetics
  • Binding Sites
  • HIV Protease / genetics
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Protein Conformation*
  • Sequence Alignment
  • Simian Immunodeficiency Virus / enzymology*

Substances

  • Aspartic Acid Endopeptidases
  • HIV Protease
  • SIV(mac) proteinase