PDBsum entry: 1gqf

Hydrolase

PDB id: 1gqf

Contents

Protein chains

265 a.a. *

Ligands

SO4 ×5

Waters ×20

* Residue conservation analysis

PDB id:

1gqf

Name:

Hydrolase

Title:

Crystal structure of human procaspase-7

Structure:

Chain: a, b

Source:

Homo sapiens. Human. Organism_taxid: 9606

Biol. unit:

Dimer (from PDB file)

Resolution:

2.9Å R-factor: 0.268 R-free: 0.285

Authors:

S.Riedl,W.Bode,P.Fuentes-Prior

Key ref:

S.J.Riedl et al. (2001). Structural basis for the activation of human procaspase-7. Proc Natl Acad Sci U S A, 98, 14790-14795. PubMed id: 11752425 DOI: 10.1073/pnas.221580098

Date:

23-Nov-01 Release date: 04-Jan-02

Protein chains

P55210  (CASP7_HUMAN) -  Caspase-7

Seq: 303 a.a.

Struc: 265 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.4.22.60 - Caspase-7.

 Gene Ontology (GO) functional annotation 

• Cellular component: cytoplasm (1 term)
• Biological process: apoptosis (2 terms)
• Biochemical function: cysteine-type peptidase activity (2 terms)

DOI no: 10.1073/pnas.221580098

Proc Natl Acad Sci U S A 98:14790-14795 (2001)

PubMed id: 11752425

Structural basis for the activation of human procaspase-7.

S.J.Riedl, P.Fuentes-Prior, M.Renatus, N.Kairies, S.Krapp, R.Huber, G.S.Salvesen, W.Bode.

ABSTRACT

Caspases form a family of proteinases required for the initiation and execution phases of apoptosis. Distinct proapoptotic stimuli lead to activation of the initiator caspases-8 and -9, which in turn activate the common executioner caspases-3 and -7 by proteolytic cleavage. Whereas crystal structures of several active caspases have been reported, no three-dimensional structure of an uncleaved caspase zymogen is available so far. We have determined the 2.9-A crystal structure of recombinant human C285A procaspase-7 and have elucidated the activation mechanism of caspases. The overall fold of the homodimeric procaspase-7 resembles that of the active tetrameric caspase-7. Each monomer is organized in two structured subdomains connected by partially flexible linkers, which asymmetrically occupy and block the central cavity, a typical feature of active caspases. This blockage is incompatible with a functional substrate binding site/active site. After proteolytic cleavage within the flexible linkers, the newly formed chain termini leave the cavity and fold outward to form stable structures. These conformational changes are associated with the formation of an intact active-site cleft. Therefore, this mechanism represents a formerly unknown type of proteinase zymogen activation.

Selected figure(s)

Figure 3.
Fig. 3. Occupancy of the central cavity by the blocking segments. (A) Section of the dimer interface region, superimposed with the well contoured lateral electron density stretches accounting for the blocking segments Lys-320-Asp326, and the disrupted central density (green). The final electron density is contoured at 1.0 . The main-chain segments are colored as in Fig. 2. The side chains of some selected residues are shown as stick models. (B) Close-up stereo view around the right-side blocking loop. The electron density for residues Ile-321 to Asp-326 contoured at 1.0 is superimposed.

Figure 5.
Fig. 5. Schematic representation of the procaspase activation mechanism. In the zymogen, both blocking segments and part of the linker occupy the central cavity, preventing intrusion of the elbow loop from the opposite monomer. Upon activation cleavage, the newly formed N and C termini turn away from the cavity crossing over each other to form stable structures. This allows the elbow loop to expand into the now empty cavity, enabling the substrate alignment segment to shift and adopt its active conformation. As a consequence, the substrate binding subsites and the active sites become functional.

Figures were selected by an automated process.