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PDBsum entry 1zcm

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protein ligands metals links
Hydrolase PDB id
1zcm
Jmol
Contents
Protein chain
321 a.a. *
Ligands
C1N
Metals
_CA ×2
Waters ×206
* Residue conservation analysis
PDB id:
1zcm
Name: Hydrolase
Title: Human calpain protease core inhibited by zllych2f
Structure: Calpain 1, large [catalytic] subunit. Chain: a. Fragment: residues 33 to 353. Synonym: calcium-activated neutral proteinase, canp, mu- type, mucanp, micromolar-calpain. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: capn1, canpl1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.00Å     R-factor:   0.182     R-free:   0.223
Authors: Q.Li,R.P.Hanzlik,R.F.Weaver,E.Schonbrunn
Key ref:
Q.Li et al. (2006). Molecular mode of action of a covalently inhibiting peptidomimetic on the human calpain protease core. Biochemistry, 45, 701-708. PubMed id: 16411745 DOI: 10.1021/bi052077b
Date:
12-Apr-05     Release date:   31-Jan-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P07384  (CAN1_HUMAN) -  Calpain-1 catalytic subunit
Seq:
Struc:
 
Seq:
Struc:
714 a.a.
321 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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/bi052077b Biochemistry 45:701-708 (2006)
PubMed id: 16411745  
 
 
Molecular mode of action of a covalently inhibiting peptidomimetic on the human calpain protease core.
Q.Li, R.P.Hanzlik, R.F.Weaver, E.Schönbrunn.
 
  ABSTRACT  
 
Calpain is a nearly ubiquitous Ca2+-activated proteolytic enzyme whose precise physiological function is unknown. However, aberrant Ca2+ homeostasis in the course of cellular injuries and certain diseases of the CNS appears to activate calpain, in turn promoting the degradation of key cytoskeletal and membrane proteins. Hyperactive calpain has also been implicated in various aging phenomena and diseases of late life. Therefore, calpain is considered a potential therapeutic target in preventing degenerations of many kinds. Despite its potential medicinal importance, known structural information about mu-calpain is limited to that from the rat enzyme. We have determined the crystal structure of the human mu-calpain protease core (hmuI-II) containing a Gly213Ala mutation and covalently inactivated by a peptidomimetic (ZLLYCH2F) at 2.0 A resolution. The methylene carbon of the inhibitor is bound to Cys115. Additional hydrogen bonding and hydrophobic interactions between active site residues and the inhibitor, including an intermolecular antiparallel beta-sheet arrangement characteristically observed with members of the papain family of cysteine proteinases, help to stabilize the complex and orient the inhibitor. The terminal ZL portion of the inhibitor is solvent-exposed and highly flexible, and is thus not involved in specific binding interactions with the enzyme. Two large enzyme regions flanking the active site are highly flexible; they may be important in recognition of calpain's natural protein substrates and in positioning them for catalysis. The implications for drug design are discussed.
 

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.  
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
18615853 L.Qin, L.Zhou, X.Wu, J.Cheng, J.Wang, Y.Du, J.Hu, M.Shen, and J.Zhou (2008).
Genetic variants in protein kinase C zeta gene and type 2 diabetes risk: a case-control study of a Chinese Han population.
  Diabetes Metab Res Rev, 24, 480-485.  
18615583 Y.Wen, H.Wang, R.MacLaren, H.Lu, X.F.Hu, and K.Cianflone (2008).
Sex steroid hormones induce acylation stimulating protein resistance in 3T3-L1 adipocytes.
  J Cell Biochem, 105, 404-413.  
18004729 Y.Wen, H.Wang, R.MacLaren, J.Wu, H.Lu, and K.Cianflone (2008).
Palmitate and oleate induction of acylation stimulating protein resistance in 3T3-L1 adipocytes and preadipocytes.
  J Cell Biochem, 104, 391-401.  
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.  
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.