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* Residue conservation analysis
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Enzyme class:
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Chains A, B, C, D:
E.C.3.4.22.38
- Cathepsin K.
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Reaction:
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Broad proteolytic activity. With small-molecule substrates and inhibitors, the major determinant of specificity is P2, which is preferably Leu, Met > Phe, and not Arg.
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Gene Ontology (GO) functional annotation
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Cellular component
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extracellular space
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3 terms
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Biological process
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bone resorption
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3 terms
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Biochemical function
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protein binding
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5 terms
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Protein Sci
8:283-290
(1999)
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PubMed id:
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Crystal structure of wild-type human procathepsin K.
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J.Sivaraman,
M.Lalumière,
R.Ménard,
M.Cygler.
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ABSTRACT
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Cathepsin K is a lysosomal cysteine protease belonging to the papain
superfamily. It has been implicated as a major mediator of osteoclastic bone
resorption. Wild-type human procathepsin K has been crystallized in a
glycosylated and a deglycosylated form. The latter crystals diffract better, to
3.2 A resolution, and contain four molecules in the asymmetric unit. The
structure was solved by molecular replacement and refined to an R-factor of
0.194. The N-terminal fragment of the proregion forms a globular domain while
the C-terminal segment is extended and shows substantial flexibility. The
proregion interacts with the enzyme along the substrate binding groove and along
the proregion binding loop (residues Ser138-Asn156). It binds to the active site
in the opposite direction to that of natural substrates. The overall binding
mode of the proregion to cathepsin K is similar to that observed in cathepsin L,
caricain, and cathepsin B, but there are local differences that likely
contribute to the specificity of these proregions for their cognate enzymes. The
main observed difference is in the position of the short helix alpha3p
(67p-75p), which occupies the S' subsites. As in the other proenzymes, the
proregion utilizes the S2 subsite for anchoring by placing a leucine side chain
there, according to the specificity of cathepsin K toward its substrate.
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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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K.Schilling,
A.Körner,
S.Sehmisch,
A.Kreusch,
R.Kleint,
Y.Benedix,
A.Schlabrakowski,
and
B.Wiederanders
(2009).
Selectivity of propeptide-enzyme interaction in cathepsin L-like cysteine proteases.
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Biol Chem, 390,
167-174.
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H.Marx,
D.Mattanovich,
and
M.Sauer
(2008).
Overexpression of the riboflavin biosynthetic pathway in Pichia pastoris.
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Microb Cell Fact, 7,
23.
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N.Mallorquí-Fernández,
S.P.Manandhar,
G.Mallorquí-Fernández,
I.Usón,
K.Wawrzonek,
T.Kantyka,
M.Solà,
I.B.Thøgersen,
J.J.Enghild,
J.Potempa,
and
F.X.Gomis-Rüth
(2008).
A new autocatalytic activation mechanism for cysteine proteases revealed by Prevotella intermedia interpain A.
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J Biol Chem, 283,
2871-2882.
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PDB codes:
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R.E.Burden,
P.Snoddy,
C.A.Jefferies,
B.Walker,
and
C.J.Scott
(2007).
Inhibition of cathepsin L-like proteases by cathepsin V propeptide.
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Biol Chem, 388,
541-545.
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G.Kaulmann,
G.J.Palm,
K.Schilling,
R.Hilgenfeld,
and
B.Wiederanders
(2006).
The crystal structure of a Cys25 -> Ala mutant of human procathepsin S elucidates enzyme-prosequence interactions.
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Protein Sci, 15,
2619-2629.
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PDB code:
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E.Wieczerzak,
E.Jankowska,
S.Rodziewicz-Motowidło,
A.Giełdoń,
J.Lagiewka,
Z.Grzonka,
M.Abrahamson,
A.Grubb,
and
D.Brömme
(2005).
Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B.
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J Pept Res, 66,
1.
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A.Rossi,
Q.Deveraux,
B.Turk,
and
A.Sali
(2004).
Comprehensive search for cysteine cathepsins in the human genome.
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Biol Chem, 385,
363-372.
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M.Cappetta,
I.Roth,
A.Díaz,
J.Tort,
and
L.Roche
(2002).
Role of the prosegment of Fasciola hepatica cathepsin L1 in folding of the catalytic domain.
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Biol Chem, 383,
1215-1221.
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S.Pietschmann,
M.Fehn,
G.Kaulmann,
I.Wenz,
B.Wiederanders,
and
K.Schilling
(2002).
Foldase function of the cathepsin S proregion is strictly based upon its domain structure.
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Biol Chem, 383,
1453-1458.
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K.Schilling,
S.Pietschmann,
M.Fehn,
I.Wenz,
and
B.Wiederanders
(2001).
Folding incompetence of cathepsin L-like cysteine proteases may be compensated by the highly conserved, domain-building N-terminal extension of the proregion.
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Biol Chem, 382,
859-865.
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J.Guay,
J.P.Falgueyret,
A.Ducret,
M.D.Percival,
and
J.A.Mancini
(2000).
Potency and selectivity of inhibition of cathepsin K, L and S by their respective propeptides.
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Eur J Biochem, 267,
6311-6318.
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T.F.Kagawa,
J.C.Cooney,
H.M.Baker,
S.McSweeney,
M.Liu,
S.Gubba,
J.M.Musser,
and
E.N.Baker
(2000).
Crystal structure of the zymogen form of the group A Streptococcus virulence factor SpeB: an integrin-binding cysteine protease.
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Proc Natl Acad Sci U S A, 97,
2235-2240.
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PDB code:
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C.M.Hosfield,
J.S.Elce,
P.L.Davies,
and
Z.Jia
(1999).
Crystal structure of calpain reveals the structural basis for Ca(2+)-dependent protease activity and a novel mode of enzyme activation.
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EMBO J, 18,
6880-6889.
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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
