Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.
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.
Abad-Zapatero
C
C
Laboratory of Protein Crystallography, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Goldman
R
R
Muchmore
S W
SW
Hutchins
C
C
Stewart
K
K
Navaza
J
J
Payne
C D
CD
Ray
T L
TL
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
D000935:Antifungal Agents; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases