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PDBsum entry 2r9f

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protein ligands metals links
Hydrolase PDB id
2r9f
Jmol
Contents
Protein chain
322 a.a. *
Ligands
K2Z
GOL ×2
Metals
_CA ×2
_CL ×3
Waters ×268
* Residue conservation analysis
PDB id:
2r9f
Name: Hydrolase
Title: Calpain 1 proteolytic core inactivated by zlak-3002, an alph ketoamide
Structure: 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-c engineered: yes
Source: Rattus norvegicus. Rat. Gene: capn1, cls1. Expressed in: escherichia coli.
Resolution:
1.60Å     R-factor:   0.191     R-free:   0.222
Authors: J.Qian,R.L.Campbell,P.L.Davies
Key ref: 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: 18702462
Date:
12-Sep-07     Release date:   26-Aug-08    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P97571  (CAN1_RAT) -  Calpain-1 catalytic subunit
Seq:
Struc:
 
Seq:
Struc:
713 a.a.
322 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   1 term 
  Biological process     proteolysis   1 term 
  Biochemical function     calcium ion binding     2 terms  

 

 
J Med Chem 51:5264-5270 (2008)
PubMed id: 18702462  
 
 
Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions.
J.Qian, D.Cuerrier, P.L.Davies, Z.Li, J.C.Powers, R.L.Campbell.
 
  ABSTRACT  
 
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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21434837 I.O.Donkor (2011).
Calpain inhibitors: a survey of compounds reported in the patent and scientific literature.
  Expert Opin Ther Pat, 21, 601-636.  
21504847 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.
  Bioorg Med Chem Lett, 21, 2850-2854.  
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.