PDBsum entry: 2ary

Hydrolase

PDB id: 2ary

Contents

Protein chains

322 a.a. *

Ligands

BME ×3

Metals

_CA ×4

Waters ×229

* Residue conservation analysis

PDB id:

2ary

Name:

Hydrolase

Title:

Catalytic domain of human calpain-1

Structure:

Calpain-1 catalytic subunit. Chain: a, b. Fragment: catalytic domain, residues 33-354. Synonym: calpain-1 large subunit, calcium-activated neutral proteinase 1, canp 1, calpain mu-type, mucanp, micromolar-calpain. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: capn1, canpl1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.40Å R-factor: 0.222 R-free: 0.264

Authors:

J.R.Walker,T.Davis,V.Lunin,E.M.Newman,F.Mackenzie,J.Weigelt, M.Sundstrom,C.Arrowsmith,A.Edwards,A.Bochkarev,S.Dhe- Paganon,Structural Genomics Consortium (Sgc)

Key ref:

T.L.Davis et al. (2007). The crystal structures of human calpains 1 and 9 imply diverse mechanisms of action and auto-inhibition. J Mol Biol, 366, 216-229. PubMed id: 17157313 DOI: 10.1016/j.jmb.2006.11.037

Date:

22-Aug-05 Release date: 30-Aug-05

Protein chains

P07384  (CAN1_HUMAN) -  Calpain-1 catalytic subunit

Seq: 714 a.a.

Struc: 322 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.22.52 - Calpain-1.
• Cofactor: Calcium

 Gene Ontology (GO) functional annotation 

• Cellular component: intracellular (1 term)
• Biological process: proteolysis (1 term)
• Biochemical function: cysteine-type endopeptidase activity (2 terms)

DOI no: 10.1016/j.jmb.2006.11.037

J Mol Biol 366:216-229 (2007)

PubMed id: 17157313

The crystal structures of human calpains 1 and 9 imply diverse mechanisms of action and auto-inhibition.

T.L.Davis, J.R.Walker, P.J.Finerty, F.Mackenzie, E.M.Newman, S.Dhe-Paganon.

ABSTRACT

Calpains are calcium activated cysteine proteases found throughout the animal, plant, and fungi kingdoms; 14 isoforms have been described in the human genome. Calpains have been implicated in multiple models of human disease; for instance, calpain 1 is activated in the brains of individuals with Alzheimer's disease, and the digestive tract specific calpain 9 is down-regulated in gastric cancer cell lines. We have solved the structures of human calpain 1 and calpain 9 protease cores using crystallographic methods; both structures have clear implications for the function of non-catalytic domains of full-length calpains in the calcium-mediated activation of the enzyme. The structure of minicalpain 1 is similar to previously solved structures of the protease core. Auto-inhibition in this system is most likely through rearrangements of a central helical/loop region near the active site cysteine, which occlude the substrate binding site. However, the structure of minicalpain 9 indicates that auto-inhibition in this enzyme is mediated through large intra-domain movements that misalign the catalytic triad. This disruption is reminiscent of the full-length inactive calpain conformation. The structures of the highly conserved, ubiquitously expressed human calpain 1 and the more tissue specific human calpain 9 indicate that although there are high levels of sequence conservation throughout the calpain family, isolated structures of family members are insufficient to explain the molecular mechanism of activation for this group of proteins.

Selected figure(s)

Figure 3.
Figure 3. The structural environment around Trp116 and the spatial relationship between α7 and α4 in human minicalpain 1. The β-ME molecule modifying the distal Cys351 residue is shown in stick representation; distances between either electrostatic pairs or water molecules are given in Angstrom units.

Figure 4.
Figure 4. The structure of human minicalpain 9. (a) The fold of human minicalpain 9 is shown in ribbon representation. The structure is colored by secondary structure elements, and the N and C termini are labeled. The catalytic triad is shown in stick representation and labeled, and the two calcium ions bound in the crystal structure are shown as yellow spheres. (b) Zoomed view of the malformed active site in human minicalpain 9. The alanine in position 195 stabilizes the formation of the α7 helix; other residues conserved between human minicalpains 1 and 2 are divergent in this family member. The distance between the catalytic and the histidine and asparagine of the catalytic triad are shown. (c) The active site of human minicalpain 1 for comparison to (b).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 366, 216-229) copyright 2007.

Figures were selected by an automated process.