PDBsum entry 1pyo

Hydrolase/hydrolase inhibitor

PDB id: 1pyo

Contents

Protein chains

159 a.a. *

98 a.a. *

Ligands

ACE-LEU-ASP-GLU-SER-ASJ ×2

Waters ×385

* Residue conservation analysis

PDB id:

1pyo

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of human caspase-2 in complex with acetyl-leu-asp- glu-ser-asp-cho

Structure:

Caspase-2. Chain: a, c. Fragment: subunit p18, sequence database residues 151-316. Synonym: casp-2, ich-1 protease, ich- 1l/1s. Engineered: yes. Caspase-2. Chain: b, d. Fragment: subunit p12, sequence database residues 331-435. Synonym: casp-2, ich-1 protease, ich- 1l/1s.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: casp2 or ich1. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Saccharomyces cerevisiae (baker's yeast). Organism_taxid: 559292.

Biol. unit:

Hexamer (from PQS)

Resolution:

1.65Å R-factor: 0.189 R-free: 0.213

Authors:

A.Schweizer,C.Briand,M.G.Grutter

Key ref:

A.Schweizer et al. (2003). Crystal structure of caspase-2, apical initiator of the intrinsic apoptotic pathway. J Biol Chem, 278, 42441-42447. PubMed id: 12920126 DOI: 10.1074/jbc.M304895200

Date:

09-Jul-03 Release date: 26-Aug-03

Protein chains

P42575  (CASP2_HUMAN) -  Caspase-2 from Homo sapiens

Seq: 452 a.a.

Struc: 159 a.a.

Protein chains

P42575  (CASP2_HUMAN) -  Caspase-2 from Homo sapiens

Seq: 452 a.a.

Struc: 98 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.3.4.22.55 - caspase-2.

DOI no: 10.1074/jbc.M304895200

J Biol Chem 278:42441-42447 (2003)

PubMed id: 12920126

Crystal structure of caspase-2, apical initiator of the intrinsic apoptotic pathway.

A.Schweizer, C.Briand, M.G.Grutter.

ABSTRACT

The cell death protease caspase-2 has recently been recognized as the most apical caspase in the apoptotic cascade ignited during cell stress signaling. Cytotoxic stress, such as that caused by cancer therapies, leads to activation of caspase-2, which acts as a direct effector of the mitochondrion-dependent apoptotic pathway resulting in programmed cell death. Here we report the x-ray structure of caspase-2 in complex with the inhibitor acetyl-Leu-Asp-Glu-Ser-Asp-aldehyde at 1.65-A resolution. Compared with other caspases, significant structural differences prevail in the active site region and the dimer interface. The structure reveals the hydrophobic properties of the S5 specificity pocket, which is unique to caspase-2, and provides the details of the inhibitor-protein interactions in subsites S1-S4. These features form the basis of caspase-2 specificity and allow the design of caspase-2-directed ligands for medical and analytical use. Another unique feature of caspase-2 is a disulfide bridge at the dimer interface, which covalently links the two monomers. Consistent with this finding, caspase-2 exists as a (p19/p12)2 dimer in solution, even in the absence of substrates or inhibitors. The intersubunit disulfide bridge stabilizes the dimeric form of caspase-2, whereas all other long prodomain caspases exist as monomers in solution, and dimer formation is driven by ligand binding. Therefore, the central disulfide bridge appears to represent a novel way of dimer stabilization in caspases.

Selected figure(s)

Figure 2.
FIG. 2. Comparison of the enzyme inhibitor interaction network of caspase-2 and caspase-3. Schematic drawing of the caspase-2 Ac-LDESD-cho inhibitor complex (a) and the caspase-3 Ac-DEVD-cho inhibitor complex (b) (1PAU [PDB] ; 37) with hydrogen bond interactions drawn as dashed lines (length: 2.6-3.4 Å). The diagram was produced by ChemDraw.

Figure 3.
FIG. 3. Binding pockets of caspase-2, caspase-3, and caspase-7. Comparison of the substrate binding region of caspase-2/Ac-LDESD-cho (a) with caspase-3/Ac-DEVD-cho (b) (1PAU [PDB] ; 37) and caspase-7/Ac-DEVD-cho (c) (1F1J [PDB] ; 35) using molecular surface representations. The inhibitors are drawn as stick models, the P5 Leu is colored in green as well as the N-terminal acetyl groups of the tetrapeptidic inhibitors. Surfaces are colored according to their electrostatic potential: positive and negative regions are indicated in blue and red, respectively. The figures were generated using the program GRASP (48).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 42441-42447) copyright 2003.

Figures were selected by an automated process.