PDBsum entry: 1k86

Apoptosis

PDB id: 1k86

Contents

Protein chains

232 a.a. *

Waters ×49

* Residue conservation analysis

PDB id:

1k86

Name:

Apoptosis

Title:

Crystal structure of caspase-7

Structure:

Caspase-7. Chain: a, b. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: caspase-7. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Dimer (from PQS)

Resolution:

2.60Å R-factor: 0.232 R-free: 0.257

Authors:

J.Chai,Q.Wu,E.Shiozaki,S.M.Srinivasa,E.S.Alnemri,Y.Shi

Key ref:

J.Chai et al. (2001). Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding. Cell, 107, 399-407. PubMed id: 11701129 DOI: 10.1016/S0092-8674(01)00544-X

Date:

23-Oct-01 Release date: 21-Nov-01

Protein chains

P55210  (CASP7_HUMAN) -  Caspase-7

Seq: 303 a.a.

Struc: 232 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: 10.1016/S0092-8674(01)00544-X

Cell 107:399-407 (2001)

PubMed id: 11701129

Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding.

J.Chai, Q.Wu, E.Shiozaki, S.M.Srinivasula, E.S.Alnemri, Y.Shi.

ABSTRACT

Apoptosis is primarily executed by active caspases, which are derived from the inactive procaspase zymogens through proteolytic cleavage. Here we report the crystal structures of a caspase zymogen, procaspase-7, and an active caspase-7 without any bound inhibitors. Compared to the inhibitor-bound caspase-7, procaspase-7 zymogen exhibits significant structural differences surrounding the catalytic cleft, which precludes the formation of a productive conformation. Proteolytic cleavage between the large and small subunits allows rearrangement of essential loops in the active site, priming active caspase-7 for inhibitor/substrate binding. Strikingly, binding by inhibitors causes a 180 degrees flipping of the N terminus in the small subunit, which interacts with and stabilizes the catalytic cleft. These analyses reveal the structural mechanisms of caspase activation and demonstrate that the inhibitor/substrate binding is a process of induced fit.

Selected figure(s)

Figure 2.
Figure 2. A Structural Mechanism for the Activation of Procaspase-7(A) Stabilization of the catalytic cleft by the loop-bundle in the active caspase-7 bound with an XIAP fragment (PDB code 1I51). The loop-bundle is nucleated by the free N terminus (L2′) of the small subunit. These interactions occur between two adjacent caspase-7 heterodimers. Fragments from these two heterodimers are colored green and blue, respectively. Their side chains are colored gold and yellow, respectively. Hydrogen bonds are represented by red dashed lines.(B) The uncleaved interdomain loop in the procaspase-7 zymogen is restrained to adopt a different set of interactions. Fragments from two adjacent heterodimers are colored gray and brown, respectively.(C) Superposition of the loop-bundle in the active caspase-7 and the corresponding regions in the procaspase-7 zymogen. Coloring scheme is the same as in (A) and (B). The orientation of active caspase-7 is the same for (A) and (C). The orientation of procaspase-7 in this panel is highly similar (a rotation of 5° along vertical axis) to that in (B).(D) Sequence alignment of the L2 loop region for caspase-3, -6, -7, and -9. The catalytic Cys is highlighted in red, while conserved residues are colored yellow. Interactions in the procaspase-7 zymogen and the XIAP-bound active caspase-7 are shown below and above the alignment, respectively. Residues that make hydrogen bonds in the loop-bundle region with their side chain and main chain groups are indicated by red arrows and red squares, respectively. Residues that make van der Waals contacts are identified by blue squares. The scissors indicate the position of activation cleavage in procaspase-7 and -3

Figure 5.
Figure 5. Schematic Diagram of Caspase Activation and Substrate/Inhibitor BindingThe active site loops in procaspase-7 zymogen are in an unproductive conformation for catalysis. The contiguous interdomain loop in the procaspase-7 zymogen locks the interdomain loop in a closed conformation and precludes a conformational change that must accompany substrate/inhibitor binding. The proteolytic cleavage after Asp198 rearranges the active site loops and produces a free N terminus in the small subunit (L2′). These changes ready the active caspase-7 for substrate/inhibitor binding, which further induces a drastic conformational switch

The above figures are reprinted by permission from Cell Press: Cell (2001, 107, 399-407) copyright 2001.

Figures were selected by an automated process.