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PDBsum entry 1zap
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Aspartic protease
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PDB id
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1zap
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Contents |
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.23.24
- candidapepsin.
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Reaction:
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Preferential cleavage at the carboxyl of hydrophobic amino acids, but fails to cleave 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-17 and 24-Phe-|-Phe-25 of insulin B chain. Activates trypsinogen, and degrades keratin.
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DOI no:
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Protein Sci
5:640-652
(1996)
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PubMed id:
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Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.
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C.Abad-Zapatero,
R.Goldman,
S.W.Muchmore,
C.Hutchins,
K.Stewart,
J.Navaza,
C.D.Payne,
T.L.Ray.
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ABSTRACT
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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.
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Selected figure(s)
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Figure 1.
Fig. 1. Stereodiagram of lectrondensity map corresponding to theinsetionat the first disulfide bond(Cys47-Cys 59)
of the SAP2X tructure. The figurecomprissresidues Ile 45-Lys 60 withthecorrespondingelectrondensity (2F, - ,; =
1 level). It illustratesthequality of the electron densityandtherigidity of the conformation. Residues are labeledsequentially
from Ile 45 to Lys 60. See Fiure for therelative disposition of this loop inrelation to the est of the structure.
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Figure 7.
Fig. 7. Schematic representation of the hydrogen bondinginteractions of he -7045 inhibitor with theproteinatoms the
SAPZX and of thedifferent enzyme pockets corresponding to theinhibitor subsites.
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(1996,
5,
640-652)
copyright 1996.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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B.Degel,
P.Staib,
S.Rohrer,
J.Scheiber,
E.Martina,
C.Büchold,
K.Baumann,
J.Morschhäuser,
and
T.Schirmeister
(2008).
Cis-Configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2.
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ChemMedChem,
3,
302-315.
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D.Imamura,
R.Zhou,
M.Feig,
and
L.Kroos
(2008).
Evidence that the Bacillus subtilis SpoIIGA protein is a novel type of signal-transducing aspartic protease.
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J Biol Chem,
283,
15287-15299.
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C.Borelli,
E.Ruge,
M.Schaller,
M.Monod,
H.C.Korting,
R.Huber,
and
K.Maskos
(2007).
The crystal structure of the secreted aspartic proteinase 3 from Candida albicans and its complex with pepstatin A.
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Proteins,
68,
738-748.
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PDB codes:
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F.Majer,
L.Pavlícková,
P.Majer,
M.Hradilek,
E.Dolejsí,
O.Hrusková-Heidingsfeldová,
and
I.Pichová
(2006).
Structure-based specificity mapping of secreted aspartic proteases of Candida parapsilosis, Candida albicans, and Candida tropicalis using peptidomimetic inhibitors and homology modeling.
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Biol Chem,
387,
1247-1254.
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M.Merkerová,
J.Dostál,
M.Hradilek,
I.Pichová,
and
O.Hrusková-Heidingsfeldová
(2006).
Cloning and characterization of Sapp2p, the second aspartic proteinase isoenzyme from Candida parapsilosis.
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FEMS Yeast Res,
6,
1018-1026.
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J.Dostál,
H.Dlouhá,
P.Malon,
I.Pichová,
and
O.Hrusková-Heidingsfeldová
(2005).
The precursor of secreted aspartic proteinase Sapp1p from Candida parapsilosis can be activated both autocatalytically and by a membrane-bound processing proteinase.
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Biol Chem,
386,
791-799.
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M.Schaller,
C.Borelli,
H.C.Korting,
and
B.Hube
(2005).
Hydrolytic enzymes as virulence factors of Candida albicans.
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Mycoses,
48,
365-377.
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J.R.Naglik,
S.J.Challacombe,
and
B.Hube
(2003).
Candida albicans secreted aspartyl proteinases in virulence and pathogenesis.
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Microbiol Mol Biol Rev,
67,
400.
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I.Pichová,
L.Pavlícková,
J.Dostál,
E.Dolejsí,
O.Hrusková-Heidingsfeldová,
J.Weber,
T.Ruml,
and
M.Soucek
(2001).
Secreted aspartic proteases of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida lusitaniae. Inhibition with peptidomimetic inhibitors.
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Eur J Biochem,
268,
2669-2677.
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N.S.Andreeva,
and
L.D.Rumsh
(2001).
Analysis of crystal structures of aspartic proteinases: on the role of amino acid residues adjacent to the catalytic site of pepsin-like enzymes.
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Protein Sci,
10,
2439-2450.
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H.C.Korting,
M.Schaller,
G.Eder,
G.Hamm,
U.Böhmer,
and
B.Hube
(1999).
Effects of the human immunodeficiency virus (HIV) proteinase inhibitors saquinavir and indinavir on in vitro activities of secreted aspartyl proteinases of Candida albicans isolates from HIV-infected patients.
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Antimicrob Agents Chemother,
43,
2038-2042.
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J.D.Tyndall,
and
D.P.Fairlie
(1999).
Conformational homogeneity in molecular recognition by proteolytic enzymes.
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J Mol Recognit,
12,
363-370.
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M.Schaller,
B.Hube,
M.W.Ollert,
W.Schäfer,
M.Borg-von Zepelin,
E.Thoma-Greber,
and
H.C.Korting
(1999).
In vivo expression and localization of Candida albicans secreted aspartyl proteinases during oral candidiasis in HIV-infected patients.
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J Invest Dermatol,
112,
383-386.
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L.Hoegl,
E.Thoma-Greber,
M.Röcken,
and
H.C.Korting
(1998).
Shift from persistent oral pseudomembranous to erythematous candidosis in a human immunodeficiency virus (HIV)-infected patient upon combination treatment with an HIV protease inhibitor.
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Mycoses,
41,
213-217.
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L.Hoegl,
E.Thoma-Greber,
M.Röcken,
and
H.C.Korting
(1998).
HIV protease inhibitors influence the prevalence of oral candidosis in HIV-infected patients: a 2-year study.
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Mycoses,
41,
321-325.
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W.L.Chaffin,
J.L.López-Ribot,
M.Casanova,
D.Gozalbo,
and
J.P.Martínez
(1998).
Cell wall and secreted proteins of Candida albicans: identification, function, and expression.
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Microbiol Mol Biol Rev,
62,
130-180.
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A.Ghadjari,
R.C.Matthews,
and
J.P.Burnie
(1997).
Epitope mapping Candida albicans proteinase (SAP 2).
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FEMS Immunol Med Microbiol,
19,
115-123.
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J.Symersky,
M.Monod,
and
S.I.Foundling
(1997).
High-resolution structure of the extracellular aspartic proteinase from Candida tropicalis yeast.
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Biochemistry,
36,
12700-12710.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
