PDBsum entry 2g8j

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Hydrolase PDB id
Protein chain
322 a.a. *
_CA ×2
Waters ×243
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Calpain 1 proteolytic core in complex with snj-1945, a alpha-ketoamide-type inhibitor.
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-calpain. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: capn1, cls1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
1.61Å     R-factor:   0.198     R-free:   0.229
Authors: D.Cuerrier,T.Moldoveanu,P.L.Davies,R.L.Campbell
Key ref:
D.Cuerrier et al. (2006). Calpain inhibition by alpha-ketoamide and cyclic hemiacetal inhibitors revealed by X-ray crystallography. Biochemistry, 45, 7446-7452. PubMed id: 16768440 DOI: 10.1021/bi060425j
02-Mar-06     Release date:   06-Jun-06    
Go to PROCHECK summary

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

 Enzyme reactions 
   Enzyme class: E.C.  - Calpain-1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Cofactor: Ca(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   1 term 
  Biological process     proteolysis   1 term 
  Biochemical function     calcium ion binding     2 terms  


DOI no: 10.1021/bi060425j Biochemistry 45:7446-7452 (2006)
PubMed id: 16768440  
Calpain inhibition by alpha-ketoamide and cyclic hemiacetal inhibitors revealed by X-ray crystallography.
D.Cuerrier, T.Moldoveanu, J.Inoue, P.L.Davies, R.L.Campbell.
Calpains are intracellular calcium-activated cysteine proteases whose unregulated proteolysis following the loss of calcium homeostasis can lead to acute degeneration during ischemic episodes and trauma, as well as Alzheimer's disease and cataract formation. The determination of the crystal structure of the proteolytic core of mu-calpain (muI-II) in a calcium-bound active conformation has made structure-guided design of active site inhibitors feasible. We present here high-resolution crystal structures of rat muI-II complexed with two reversible calpain-specific inhibitors employing cyclic hemiacetal (SNJ-1715) and alpha-ketoamide (SNJ-1945) chemistries that reveal new details about the interactions of inhibitors with this enzyme. The SNJ-1715 complex confirms that the free aldehyde is the reactive species of the cornea-permeable cyclic hemiacetal. The alpha-ketoamide warhead of SNJ-1945 binds with the hydroxyl group of the tetrahedral adduct pointing toward the catalytic histidine rather than the oxyanion hole. The muI-II-SNJ-1945 complex shows residue Glu261 displaced from the S1' site by the inhibitor, resulting in an extended "open" conformation of the domain II gating loop and an unobstructed S1' site. This conformation offers an additional template for structure-based drug design extending to the primed subsites. An important role for the highly conserved Glu261 is proposed.

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.  
19857102 H.Ma, A.Tochigi, T.R.Shearer, and M.Azuma (2009).
Calpain inhibitor SNJ-1945 attenuates events prior to angiogenesis in cultured human retinal endothelial cells.
  J Ocul Pharmacol Ther, 25, 409-414.  
18327891 B.T.Gonçalves, P.M.Esteves, A.C.Pinto, C.R.Kaiser, F.L.da Silva, E.Miguez, and J.F.da Silva (2008).
Anisotropic and hydrogen bonding effects in phenylglyoxamides and mandelamides: theoretical and NMR conformational evaluation.
  Magn Reson Chem, 46, 418-426.  
18636690 I.O.Donkor, H.Assefa, and J.Liu (2008).
Structural basis for the potent calpain inhibitory activity of peptidyl alpha-ketoacids.
  J Med Chem, 51, 4346-4350.  
18694642 I.O.Donkor, and R.Korukonda (2008).
Synthesis and calpain inhibitory activity of peptidomimetic compounds with constrained amino acids at the P2 position.
  Bioorg Med Chem Lett, 18, 4806-4808.  
18702462 J.Qian, D.Cuerrier, P.L.Davies, Z.Li, J.C.Powers, and R.L.Campbell (2008).
Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions.
  J Med Chem, 51, 5264-5270.
PDB codes: 2r9c 2r9f
18348880 M.Azuma, and T.R.Shearer (2008).
The role of calcium-activated protease calpain in experimental retinal pathology.
  Surv Ophthalmol, 53, 150-163.  
17218315 D.Cuerrier, T.Moldoveanu, R.L.Campbell, J.Kelly, B.Yoruk, S.H.Verhelst, D.Greenbaum, M.Bogyo, and P.L.Davies (2007).
Development of calpain-specific inactivators by screening of positional scanning epoxide libraries.
  J Biol Chem, 282, 9600-9611.
PDB codes: 2nqg 2nqi
17608959 D.E.Croall, and K.Ersfeld (2007).
The calpains: modular designs and functional diversity.
  Genome Biol, 8, 218.  
18180198 H.K.Lorenzo, and S.A.Susin (2007).
Therapeutic potential of AIF-mediated caspase-independent programmed cell death.
  Drug Resist Updat, 10, 235-255.  
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.