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PDBsum entry 2r9c
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Calpain 1 proteolytic core inactivated by zlak-3001, an alpha- ketoamide
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Structure:
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Calpain-1 catalytic subunit. Chain: a. Fragment: residues: 27-356. Synonym: calpain-1 large subunit, calcium-activated neutral proteinase 1, canp 1, calpain mu-type, mucanp, micromolar-calpain. Engineered: yes
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Source:
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Rattus norvegicus. Rat. Gene: capn1, cls1. Expressed in: escherichia coli.
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Resolution:
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1.80Å
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R-factor:
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0.158
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R-free:
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0.196
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Authors:
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J.Qian,R.L.Campbell,P.L.Davies
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Key ref:
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J.Qian
et al.
(2008).
Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions.
J Med Chem,
51,
5264-5270.
PubMed id:
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Date:
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12-Sep-07
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Release date:
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26-Aug-08
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PROCHECK
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Headers
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References
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P97571
(CAN1_RAT) -
Calpain-1 catalytic subunit from Rattus norvegicus
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Seq:
Struc:
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713 a.a.
322 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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J Med Chem
51:5264-5270
(2008)
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PubMed id:
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Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions.
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J.Qian,
D.Cuerrier,
P.L.Davies,
Z.Li,
J.C.Powers,
R.L.Campbell.
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ABSTRACT
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Calpains are intracellular cysteine proteases that catalyze the cleavage of
target proteins in response to Ca(2+) signaling. When Ca(2+) homeostasis is
disrupted, calpain overactivation causes unregulated proteolysis, which can
contribute to diseases such as postischemic injury and cataract formation.
Potent calpain inhibitors exist, but of these many cross-react with other
cysteine proteases and will need modification to specifically target calpain.
Here, we present crystal structures of rat calpain 1 protease core (muI-II)
bound to two alpha-ketoamide-based calpain inhibitors containing adenyl and
piperazyl primed-side extensions. An unexpected aromatic-stacking interaction is
observed between the primed-side adenine moiety and the Trp298 side chain. This
interaction increased the potency of the inhibitor toward muI-II and
heterodimeric m-calpain. Moreover, stacking orients the adenine such that it can
be used as a scaffold for designing novel primed-side address regions, which
could be incorporated into future inhibitors to enhance their calpain
specificity.
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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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I.O.Donkor
(2011).
Calpain inhibitors: a survey of compounds reported in the patent and scientific literature.
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Expert Opin Ther Pat,
21,
601-636.
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Y.J.Yoo,
D.H.Nam,
S.Y.Jung,
J.W.Jang,
H.J.Kim,
C.Jin,
A.N.Pae,
and
Y.S.Lee
(2011).
Synthesis of cinnamoyl ketoamides as hybrid structures of antioxidants and calpain inhibitors.
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Bioorg Med Chem Lett,
21,
2850-2854.
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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.
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Links
