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PDBsum entry 1spj
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References listed in PDB file
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Key reference
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Title
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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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Authors
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G.Laxmikanthan,
S.I.Blaber,
M.J.Bernett,
I.A.Scarisbrick,
M.A.Juliano,
M.Blaber.
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Ref.
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Proteins, 2005,
58,
802-814.
[DOI no: ]
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PubMed id
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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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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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