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PDBsum entry 2zck
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Immune system
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PDB id
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2zck
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Contents |
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237 a.a.
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218 a.a.
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230 a.a.
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References listed in PDB file
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Key reference
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Title
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Crystal structure of a ternary complex between human prostate-Specific antigen, Its substrate acyl intermediate and an activating antibody.
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Authors
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R.Ménez,
S.Michel,
B.H.Muller,
M.Bossus,
F.Ducancel,
C.Jolivet-Reynaud,
E.A.Stura.
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Ref.
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J Mol Biol, 2008,
376,
1021-1033.
[DOI no: ]
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PubMed id
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Abstract
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Human prostate-specific antigen (PSA or KLK3) is an important marker for the
diagnosis and management of prostate cancer. This is an androgen-regulated
glycoprotein of the kallikrein-related protease family secreted by prostatic
epithelial cells. Its physiological function is to cleave semenogelins in the
seminal coagulum and its enzymatic activity is strongly modulated by zinc ions.
Here we present the first crystal structure of human PSA in complex with
monoclonal antibody (mAb) 8G8F5 that enhances its enzymatic activity. The mAb
recognizes an epitope composed of five discontinuous segments including residues
from the kallikrein loop and stabilizes PSA in an "open and active conformation"
that accelerates catalysis. We also present the crystal structure of PSA in
complex with both the mAb 8G8F5 and a fluorogenic substrate Mu-KGISSQY-AFC,
derived from semenogelin I. By exploiting the inhibition of PSA by zinc ions, we
were able to obtain a substrate acyl intermediate covalently linked to the
catalytic serine, at pH 7.3 but not at pH 5.5. Moreover, the inhibition of PSA
activity by zinc was found to be modulated by pH variations but not by the
antibody binding. The correlation of the different data with the physiological
conditions under which PSA can cleave semenogelins is discussed.
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Figure 2.
Fig. 2. Details of the Fab′ 8G8F5 epitope. (a) Interactions
of PSA (pink) with 8G8F5 heavy chain (dark blue). (b)
Interactions of PSA (pink) with 8G8F5 light chain (blue).
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Figure 5.
Fig. 5. Crystallographic dimer in PSA and HPK. (a) The dimer
for PSA. The kallikrein loop is shown in dark green, the
substrate in light green sticks and the carbohydrate moieties in
CPK (beige and red). (b) PSA dimer (yellow and pink as in a) and
crystal contacts with the antibody heavy chain (dark blue)
showing the relationship between the substrate (CPK, light
green) and the CH1 domain C-terminus bound by PSA (dark blue
sticks). (c) The dimer for HPK.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
376,
1021-1033)
copyright 2008.
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