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PDBsum entry 1spj
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.21.35
- tissue kallikrein.
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Reaction:
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Preferential cleavage of Arg-|-Xaa bonds in small molecule substrates. Highly selective action to release kallidin (lysyl-bradykinin) from kininogen involves hydrolysis of Met-|-Xaa or Leu-|-Xaa. The rat enzyme is unusual in liberating bradykinin directly from autologous kininogens by cleavage at two Arg-|-Xaa bonds.
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DOI no:
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Proteins
58:802-814
(2005)
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PubMed id:
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1.70 A X-ray structure of human apo kallikrein 1: structural changes upon peptide inhibitor/substrate binding.
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G.Laxmikanthan,
S.I.Blaber,
M.J.Bernett,
I.A.Scarisbrick,
M.A.Juliano,
M.Blaber.
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ABSTRACT
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Human kallikreins are serine proteases that comprise a recently identified large
and closely related 15-member family. The kallikreins include both regulatory-
and degradative-type proteases, impacting a variety of physiological processes
including regulation of blood pressure, neuronal health, and the inflammatory
response. While the function of the majority of the kallikreins remains to be
elucidated, two members are useful biomarkers for prostate cancer and several
others are potentially useful biomarkers for breast cancer, Alzheimer's, and
Parkinson's disease. Human tissue kallikrein (human K1) is the best functionally
characterized member of this family, and is known to play an important role in
blood pressure regulation. As part of this function, human K1 exhibits unique
dual-substrate specificity in hydrolyzing low molecular weight kininogen between
both Arg-Ser and Met-Lys sequences. We report the X-ray crystal structure of
mature, active recombinant human apo K1 at 1.70 A resolution. The active site
exhibits structural features intermediate between that of apo and pro forms of
known kallikrein structures. The S2 to S2' pockets demonstrate a variety of
conformational changes in comparison to the porcine homolog of K1 in complex
with peptide inhibitors, including the displacement of an extensive solvent
network. These results indicate that the binding of a peptide substrate
contributes to a structural rearrangement of the active-site Ser 195 resulting
in a catalytically competent juxtaposition with the active-site His 57. The
solvent networks within the S1 and S1' pockets suggest how the Arg-Ser and
Met-Lys dual substrate specificity of human K1 is accommodated.
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Selected figure(s)
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Figure 2.
Figure 2. Relaxed stereo diagram ribbon drawing of the human
apo K1 structure (light grey) and the overlaid kallikrein loop
regions of horse K3 (1GVZ, magenta), porcine K1 (2PKA, red),
mouse GK3 (1SGF, blue), mouse GK13 (1AO5, green) and rat GK2
(1TON, yellow), with the human K1 kallikrein loop indicated in
dark grey. The active site His 57, Asp 102, and Ser 195 residues
in human K1, as well as the Asp 189 at the base of the S1 pocket
are indicated in wire frame representation. The location of the
S1 and S1  pockets
are indicated. The carbohydrate moiety attached to Asn 95,
observed in the human K1, mouse GK3 and mouse GK13 structures,
is also indicated in wire frame shown.
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Figure 3.
Figure 3. Top: relaxed stereo diagram of the active site of
human apo K1, with the active site Ser 195 gauche+ rotamer
shown, overlaid with the active site in mouse apo K8 (1NPM;
grey). Bottom: relaxed stereo diagram of the active site of
human apo K1, with the active site Ser 195 gauche- rotamer
shown, overlaid with the active site of pro human K6 (1GVL;
grey).
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2005,
58,
802-814)
copyright 2005.
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Figures were
selected
by the author.
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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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A.Pavlopoulou,
G.Pampalakis,
I.Michalopoulos,
and
G.Sotiropoulou
(2010).
Evolutionary history of tissue kallikreins.
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PLoS One,
5,
e13781.
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P.Goettig,
V.Magdolen,
and
H.Brandstetter
(2010).
Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).
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Biochimie,
92,
1546-1567.
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G.Sotiropoulou,
G.Pampalakis,
and
E.P.Diamandis
(2009).
Functional roles of human kallikrein-related peptidases.
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J Biol Chem,
284,
32989-32994.
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A.G.Vandell,
N.Larson,
G.Laxmikanthan,
M.Panos,
S.I.Blaber,
M.Blaber,
and
I.A.Scarisbrick
(2008).
Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines.
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J Neurochem,
107,
855-870.
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A.R.Lima,
F.M.Alves,
P.F.Angelo,
D.Andrade,
S.I.Blaber,
M.Blaber,
L.Juliano,
and
M.A.Juliano
(2008).
S(1)' and S(2)' subsite specificities of human plasma kallikrein and tissue kallikrein 1 for the hydrolysis of peptides derived from the bradykinin domain of human kininogen.
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Biol Chem,
389,
1487-1494.
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H.Koistinen,
G.Wohlfahrt,
J.M.Mattsson,
P.Wu,
J.Lahdenperä,
and
U.H.Stenman
(2008).
Novel small molecule inhibitors for prostate-specific antigen.
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Prostate,
68,
1143-1151.
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H.X.Li,
B.Y.Hwang,
G.Laxmikanthan,
S.I.Blaber,
M.Blaber,
P.A.Golubkov,
P.Ren,
B.L.Iverson,
and
G.Georgiou
(2008).
Substrate specificity of human kallikreins 1 and 6 determined by phage display.
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Protein Sci,
17,
664-672.
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J.A.Clements
(2008).
Reflections on the tissue kallikrein and kallikrein-related peptidase family - from mice to men - what have we learnt in the last two decades?
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Biol Chem,
389,
1447-1454.
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M.Debela,
N.Beaufort,
V.Magdolen,
N.M.Schechter,
C.S.Craik,
M.Schmitt,
W.Bode,
and
P.Goettig
(2008).
Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7.
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Biol Chem,
389,
623-632.
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C.A.Borgoño,
I.P.Michael,
N.Komatsu,
A.Jayakumar,
R.Kapadia,
G.L.Clayman,
G.Sotiropoulou,
and
E.P.Diamandis
(2007).
A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation.
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J Biol Chem,
282,
3640-3652.
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H.Yoon,
G.Laxmikanthan,
J.Lee,
S.I.Blaber,
A.Rodriguez,
J.M.Kogot,
I.A.Scarisbrick,
and
M.Blaber
(2007).
Activation profiles and regulatory cascades of the human kallikrein-related peptidases.
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J Biol Chem,
282,
31852-31864.
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I.Botos,
and
A.Wlodawer
(2007).
The expanding diversity of serine hydrolases.
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Curr Opin Struct Biol,
17,
683-690.
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M.Debela,
P.Hess,
V.Magdolen,
N.M.Schechter,
T.Steiner,
R.Huber,
W.Bode,
and
P.Goettig
(2007).
Chymotryptic specificity determinants in the 1.0 A structure of the zinc-inhibited human tissue kallikrein 7.
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Proc Natl Acad Sci U S A,
104,
16086-16091.
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PDB codes:
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C.D.Petraki,
P.A.Papanastasiou,
V.N.Karavana,
and
E.P.Diamandis
(2006).
Cellular distribution of human tissue kallikreins: immunohistochemical localization.
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Biol Chem,
387,
653-663.
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M.Debela,
V.Magdolen,
N.Schechter,
M.Valachova,
F.Lottspeich,
C.S.Craik,
Y.Choe,
W.Bode,
and
P.Goettig
(2006).
Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences.
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J Biol Chem,
281,
25678-25688.
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N.Heuzé-Vourc'h,
M.Aïnciburu,
C.Planque,
M.Brillard-Bourdet,
C.Ott,
C.Jolivet-Reynaud,
and
Y.Courty
(2006).
Recombinant kallikrein expression: site-specific integration for hK6 production in human cells.
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Biol Chem,
387,
687-695.
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P.F.Angelo,
A.R.Lima,
F.M.Alves,
S.I.Blaber,
I.A.Scarisbrick,
M.Blaber,
L.Juliano,
and
M.A.Juliano
(2006).
Substrate specificity of human kallikrein 6: salt and glycosaminoglycan activation effects.
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J Biol Chem,
281,
3116-3126.
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T.Kishi,
S.M.Cloutier,
C.Kündig,
D.Deperthes,
and
E.P.Diamandis
(2006).
Activation and enzymatic characterization of recombinant human kallikrein 8.
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Biol Chem,
387,
723-731.
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J.Tang,
C.L.Yu,
S.R.Williams,
E.Springman,
D.Jeffery,
P.A.Sprengeler,
A.Estevez,
J.Sampang,
W.Shrader,
J.Spencer,
W.Young,
M.McGrath,
and
B.A.Katz
(2005).
Expression, crystallization, and three-dimensional structure of the catalytic domain of human plasma kallikrein.
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J Biol Chem,
280,
41077-41089.
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PDB codes:
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N.L.Clark,
and
W.J.Swanson
(2005).
Pervasive adaptive evolution in primate seminal proteins.
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PLoS Genet,
1,
e35.
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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
