PDBsum entry 2p2c

Hydrolase

PDB id: 2p2c

Contents

Protein chains

(+ 0 more) 162 a.a. *

(+ 0 more) 96 a.a. *

(+ 0 more) 158 a.a. *

Waters ×29

* Residue conservation analysis

PDB id:

2p2c

Name:

Hydrolase

Title:

Inhibition of caspase-2 by a designed ankyrin repeat protein (darpin)

Structure:

Caspase-2. Chain: a, c, e, g, i, k. Fragment: residues 167-333. Caspase-2. Chain: b, d, f, h, j, l. Fragment: residues 348-452. Engineered: yes. Caspase-2. Chain: p, q, r, s, t, u.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Strain: bl21(de3). Gene: casp2. Gene: casp2

Resolution:

3.24Å R-factor: 0.262 R-free: 0.305

Authors:

H.Roschitzki Voser,C.Briand,G.Capitani,M.G.Gruetter

Key ref:

A.Schweizer et al. (2007). Inhibition of Caspase-2 by a Designed Ankyrin Repeat Protein: Specificity, Structure, and Inhibition Mechanism. Structure, 15, 625-636. PubMed id: 17502107 DOI: 10.1016/j.str.2007.03.014

Date:

07-Mar-07 Release date: 22-May-07

Protein chains

P42575  (CASP2_HUMAN) -  Caspase-2 from Homo sapiens

Seq: 452 a.a.

Struc: 162 a.a.*

Protein chains

P42575  (CASP2_HUMAN) -  Caspase-2 from Homo sapiens

Seq: 452 a.a.

Struc: 96 a.a.

Protein chains

No UniProt id for this chain

Struc: 158 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.3.4.22.55 - caspase-2.

DOI no: 10.1016/j.str.2007.03.014

Structure 15:625-636 (2007)

PubMed id: 17502107

Inhibition of Caspase-2 by a Designed Ankyrin Repeat Protein: Specificity, Structure, and Inhibition Mechanism.

A.Schweizer, H.Roschitzki-Voser, P.Amstutz, C.Briand, M.Gulotti-Georgieva, E.Prenosil, H.K.Binz, G.Capitani, A.Baici, A.Pl?ckthun, M.G.Gr?tter.

ABSTRACT

Specific and potent caspase inhibitors are indispensable for the dissection of the intricate pathways leading to apoptosis. We selected a designed ankyrin repeat protein (DARPin) from a combinatorial library that inhibits caspase-2 in vitro with a subnanomolar inhibition constant and, in contrast to the peptidic caspase inhibitors, with very high specificity for this particular caspase. The crystal structure of this inhibitor (AR_F8) in complex with caspase-2 reveals the molecular basis for the specificity and, together with kinetic analyses, the allosteric mechanism of inhibition. The structure also shows a conformation of the active site that can be exploited for the design of inhibitory compounds. AR_F8 is a specific inhibitor of an initiator caspase and has the potential to help identify the function of caspase-2 in the complex biological apoptotic signaling network.

Selected figure(s)

Figure 2.
Figure 2. Stereo Representation of the Structure of the Caspase-2/AR_F8 Complex
Caspase-2 is shown in dark blue (α subunit) and light blue (β subunit), and AR_F8 is shown in salmon. AR_F8 is bound to the back side of the active-site-forming loop 381 (see Figure 5C) of each caspase-2 monomer. Termini and loops affected by binding of AR_F8 are shown in red. The active-site cysteine (Cys285) and the intersubunit disulfide bond are shown in yellow.

Figure 3.
Figure 3. Molecular Interactions between AR_F8 and Caspase-2
Stereo representation of the caspase-2/AR_F8 interface rotated vert, similar 90° from the standard orientation, viewed from the back plane of the caspase, displaying hydrogen bonds (green, dotted lines) and hydrophobic interactions. Interacting residues of AR_F8 are shown in red; those of caspase-2 are shown in blue.

The above figures are reprinted by permission from Cell Press: Structure (2007, 15, 625-636) copyright 2007.

Figures were selected by an automated process.