PDBsum entry: 1f9e

Hydrolase/hydrolase inhibitor

PDB id: 1f9e

Contents

Protein chains

(+ 0 more) 153 a.a. *

(+ 0 more) 89 a.a. *

Ligands

PHQ-ASP-GLU-VAL-ASA ×6

Waters ×47

* Residue conservation analysis

PDB id:

1f9e

Name:

Hydrolase/hydrolase inhibitor

Title:

Caspase-8 specificity probed at subsite s4: crystal structur caspase-8-z-devd-cho

Structure:

Caspase-8 alpha chain. Chain: a, c, e, g, i, k. Engineered: yes. Caspase-8 beta chain. Chain: b, d, f, h, j, l. Engineered: yes. (Phq)devd. Chain: q, r, s, t, u, v. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: chemically synthesized

Biol. unit:

Hexamer (from PQS)

Resolution:

2.90Å R-factor: 0.241 R-free: 0.289

Authors:

H.Blanchard,M.Donepudi,M.Tschopp,L.Kodandapani,J.C.Wu,M.G.Gr

Key ref:

H.Blanchard et al. (2000). Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex. J Mol Biol, 302, 9. PubMed id: 10964557 DOI: 10.1006/jmbi.2000.4041

Date:

10-Jul-00 Release date: 10-Jul-01

Protein chains

Q14790  (CASP8_HUMAN) -  Caspase-8

Seq: 479 a.a.

Struc: 153 a.a.*

Protein chains

Q14790  (CASP8_HUMAN) -  Caspase-8

Seq: 479 a.a.

Struc: 89 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F, G, H, I, J, K, L: E.C.3.4.22.61 - Caspase-8.

 Gene Ontology (GO) functional annotation 

• Biological process: apoptosis (2 terms)
• Biochemical function: cysteine-type peptidase activity (2 terms)

DOI no: 10.1006/jmbi.2000.4041

J Mol Biol 302:9 (2000)

PubMed id: 10964557

Caspase-8 specificity probed at subsite S(4): crystal structure of the caspase-8-Z-DEVD-cho complex.

H.Blanchard, M.Donepudi, M.Tschopp, L.Kodandapani, J.C.Wu, M.G.Grütter.

ABSTRACT

Caspase-8 is an initiator enzyme in the Fas-mediated pathway of which the downstream executioner caspase-3 is a physiological target. Caspases are cysteine proteases that are specific for substrates with an aspartic acid residue at the P(1) position and have an optimal recognition motif that incorporates four amino acid residues N-terminal to the cleavage site. Caspase-8 has been classified as a group III caspase member because it shows a preference for a small hydrophobic residue at the P(4) substrate position. We report the X-ray crystallographic structure of caspase-8 in complex with benzyloxycarbonyl-Asp-Glu-Val-Asp-aldehyde (Z-DEVD), a specific group II caspase inhibitor. The structure shows that the inhibitor interacts favourably with the enzyme in subsite S(4). Kinetic data reveal that Z-DEVD (K(i) 2 nM) is an almost equally potent inhibitor of caspase-8 as the specific group III inhibitor Boc-IETD-aldehyde (K(i) 1 nM). In view of this finding, the original classification of caspases into three specificity groups needs to be modified, at least for caspase-8, which tolerates small hydrophobic residues as well as the acidic residue Asp in subsite S(4). We propose that the subsite S(3) must be considered as an important specificity-determining factor.

Selected figure(s)

Figure 2.
Figure 2. A diagram of Z-DEVD hydrogen bond interactions with caspase-8. Hydrogen bonds are shown as broken lines. This diagram was produced in ChemDraw.

Figure 3.
Figure 3. Stereoview of the superposition of caspase-8-Z-DEVD onto caspase-8-Z-EVD highlighting the hydrogen bond interaction at subsite S[3]. Superposition was done using the C^a atoms of the conserved subsite S[1] active-site residues Cys285, His237 and Arg341, and was extended for all atoms in a (p18/p12)[2] subunit using LSQMAN [Kleywegt and Jones 1994]. Shown in green is the caspase-8-Z-EVD structure and its hydrogen bond interactions [Blanchard et al 1999]. Caspase-8-Z-DEVD is shown in gold. Both inhibitors are shown in atom colours as ball and stick representations. The structures are depicted as main-chain ball and stick representations with all atoms shown for residues belonging to Loop-1; the hydrogen bond is depicted as dotted spheres and the Figure was produced in Setor [Evans 1993].

The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 302, 9-0) copyright 2000.

Figures were selected by an automated process.