title: Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.
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.
authors.affiliation: Laboratory of Protein Crystallography, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
authors.forename: C
authors.initials: C
authors.lastname: Abad-Zapatero
authors.forename: R
authors.initials: R
authors.lastname: Goldman
authors.forename: S W
authors.initials: SW
authors.lastname: Muchmore
authors.forename: C
authors.initials: C
authors.lastname: Hutchins
authors.forename: K
authors.initials: K
authors.lastname: Stewart
authors.forename: J
authors.initials: J
authors.lastname: Navaza
authors.forename: C D
authors.initials: CD
authors.lastname: Payne
authors.forename: T L
authors.initials: TL
authors.lastname: Ray
mesh_terms: D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000138:chemical synthesis*; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002176:Candida albicans / Q000201:enzymology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D000935:Antifungal Agents; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases