Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents

Protein Sci. 1996 Apr;5(4):640-52. doi: 10.1002/pro.5560050408.

Abstract

The three-dimensional structure of a secreted aspartic protease from Candida albicans complexed with a potent inhibitor reveals variations on the classical aspartic protease theme that dramatically alter the specificity of this class of enzymes. The structure presents: (1) an 8-residue insertion near the first disulfide (Cys 45-Cys 50, pepsin numbering) that results in a broad flap extending toward the active site; (2) a 7-residue deletion replacing helix hN2 (Ser 110-Tyr 114), which enlarges the S3 pocket; (3) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and (4) an ordered 11-residue addition at the carboxy terminus. The inhibitor binds in an extended conformation and presents a branched structure at the P3 position. The implications of these findings for the design of potent antifungal agents are discussed.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antifungal Agents / chemical synthesis*
  • Aspartic Acid Endopeptidases / chemistry*
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • Candida albicans / enzymology*
  • Crystallography, X-Ray
  • Drug Design*
  • Molecular Sequence Data
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / metabolism
  • Protein Conformation

Substances

  • Antifungal Agents
  • Protease Inhibitors
  • Aspartic Acid Endopeptidases