Table 2. Structures of caspase catalytic domains deposited with the Protein Data Bank*.
*Released before August 15, 2004. Eight structures of caspase-1 (PDB entries 1RWK, 1RWM, 1RWN, 1RWO, 1RWP, 1RWV, 1RWX and 1RWW), as well as two structures of caspase-7 (1SHJ and 1SHL), in complex with different inhibitors have not yet been released. PDB entries are linked to the supplemental co-ordinate files (http://www.BiochemJ.org/bj/384/bj3840201add.htm) converted into the caspase-1 numbering system. Abbreviations: Ac, acetyl; BOP, 1-bromo-4-methoxybenzene; CHO, aldehyde; dcmk, dichloromethyl ketone; fmk, fluoromethyl ketone; IL, interleukin; PTF, [(methylsulphanyl)methyl]benzene; Z, benzyloxycarbonyl.
| Protein | Entry/Resolution | Comments | Ref. |
|---|---|---|---|
| Caspase-1 | 1ICE/2.60 Å | Bound to Ac-YVAD-CHO. First structure of a caspase. The bound aldehyde mimics the activation cleavage site in pro-IL-1β. | [7] |
| Caspase-1 | 1IBC/2.73 Å | Bound to Ac-WEHD-CHO. Highly potent inhibitor (Ki 56 pM) identified in combinatorial screening. | [74] |
| Caspase-1 | 1BMQ/2.50 Å | Bound to the irreversible inhibitor (3S)-N-methanesulphonyl-3-({1-[N-(2-naphthoyl)-L-Val]-L-Pro}amino)-4-oxobutanamide. First example of an inhibitor that lacks an acidic carboxylate at P1. | [300] |
| Caspase-1 | 1SC1/2.60 Å | Free C285A mutant. Loop bundle formed, but active site disrupted (‘closed’ conformation). | [301] |
| Caspase-1 | 1SC3/1.80 Å | C285A mutant in complex with malonate. The malonate moiety binds tightly in the S1 pocket, inducing the active (‘open’) conformation. | [301] |
| Caspase-1 | 1SC4/2.10 Å | C285A mutant, after removal of malonate (see 1SC3). Active site disrupted, 341-loop disordered. | [301] |
| Caspase-2 | 1PYO/1.65 Å | Bound to Ac-LDESD-CHO. Disulphide-linked dimer (C-390−C-390′). Subsite S5 occupied. | [75] |
| Caspase-3 | 1QX3/1.90 Å | Unliganded caspase. The Y338 side chain occludes the S2 pocket. | [67] |
| Caspase-3 | 1GFW/2.80 Å | Bound to the reversible, competitive non-peptide inhibitor 1-methyl-5-(2-phenoxymethylpyrrolidine-1-sulphonyl)-1h-indole-2,3-dione. Binds primarily to the S2, but not the S1 pocket. | [302] |
| Caspase-3 | 1CP3/2.30 Å | Bound to Ac-DVAD-fmk. Oxyanion hole occupied by ketone oxygen. | [10] |
| Caspase-3 | 1PAU/2.50 Å | Bound to Ac-DEVD-CHO. First structure of an effector caspase. | [76] |
| Caspase-3 | 1NME/1.60 Å | Bound to a non-peptide inhibitor identified using ‘extended tethering’, formed by a 3-(2-mercapto-acetylamino)-4-oxopentanoic acid moiety (occupies S1 pocket) and a 2-hydroxy-5-(2-mercapto-ethylsulphamoyl)-benzoic acid moiety (S4 pocket). | [303] |
| Caspase-3 | 1NMQ/2.40 Å | Bound to 3-(3-{2-[(5-methanesulphonylthiophene-2-carbonyl)amino]ethyldisulphanylmethyl}benzenesulphonylamino)-4-oxo-pentanoic acid. | [303] |
| Caspase-3 | 1NMS/1.70 Å | Bound to 5-[4-(1-carboxymethyl-2-oxopropylcarbamoyl)benzylsulphamoyl]-2-hydroxybenzoic acid. | [303] |
| Caspase-3 | 1RE1/2.50 Å | Bound to (3S)-3-{[(5-bromopyridin-3-yl)carbonyl]amino}-4-oxobutanoic acid. Caspase Y338 fills the S2 pocket as in 1QX3, and interacts with the pyridyl ring of the inhibitor. | [68] |
| Caspase-3 | 1RHJ/2.20 Å | Bound to 3-(2-{5-tert-butyl-3-[(4-methylfurazan-3-ylmethyl)amino]-2-oxo-2H-pyrazin-1-yl}butyrylamino)-5-(hexylmethylamino)-4-oxopentanoic acid. Alkylamine moiety not visible in S1′ pocket. | |
| Furazan moiety makes significant contribution to binding strength (S4 pocket). | [68] | ||
| Caspase-3 | 1RHK/2.50 Å | Bound to the phenylpropyl ketone derivative of Ac-DEVD-CHO. Binding to S1′ subsite increases inhibitor potency by 50-fold. | [68] |
| Caspase-3 | 1RHM/2.50 Å | Bound to 4-[5-(2-carboxy-1-formylethylcarbamoyl)pyridin-3-yl]benzoic acid. Caspase Y338 fills the S2 pocket and interacts with the pyridyl ring of the inhibitor. | |
| First description of a edge-to-face interaction between an inhibitor bromoanisole moiety and indole moiety of W-340. | [68] | ||
| Caspase-3 | 1RHQ/3.00 Å | Bound to Ac-BOP-PTF. Conversion of P1′ alkyl linker into a thioether increases binding affinity (also valid for 1RHR, 1RHU). | [68] |
| Caspase-3 | 1RHR/3.00 Å | Bound to (3S)-5-[(2-chloro-6-fluorobenzyl)sulphanyl]-3-{[N-({2-ethoxy-5-[(1E)-3-methoxy-3-oxoprop-1-enyl]phenyl}acetyl)-D-valyl]amino}-4-oxopentanoic acid. Benzene derivative partially disordered in S1′ pocket. | [68] |
| Caspase-3 | 1RHU/2.50 Å | Bound to (3S)-3-[({(2S)-5-[(N-acetyl-L-α-aspartyl)amino]-4-oxo-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indol-2-yl}-carbonyl)amino]-5-(benzylsulphanyl)-4-oxopentanoic acid. | [68] |
| Caspase-3 | 1I3O/2.70 Å | Complex with XIAP (BIR2 domain and linker to BIR1). Parallel binding mode, BIR domain defined. | [255] |
| Caspase-7 | 1F1J/2.35 Å | Bound to Ac-DEVD-CHO. First structure of active caspase-7. | [63] |
| Caspase-7 | 1I51/2.45 Å | Complex with XIAP (BIR2 domain and linker to BIR1). Parallel binding mode. BIR domain flexibly disordered | [133] |
| Caspase-7 | 1I4O/2.40 Å | Complex with XIAP (BIR2 domain and linker to BIR1). Parallel binding mode. BIR domain flexibly disordered. | [134] |
| Caspase-7 | 1KMC/2.90 Å | Complex with XIAP (BIR2 domain and linker to BIR1). Parallel binding mode. BIR domain flexibly disordered. | † |
| Caspase-7 | 1K86/2.60 Å | Free caspase. Active site region unoccupied. The catalytic machinery is not completely formed. | [11] |
| Procaspase-7 | 1GQF/2.90 Å | Free zymogen. Disordered substrate-binding loops, intersubunit linker partially inserted in central cavity. | [124] |
| Procaspase-7 | 1K88/2.70 Å | Free zymogen. Disordered substrate-binding loops, intersubunit linker partially inserted in central cavity. | [11] |
| Caspase-8 | 1QTN/1.20 Å | Bound to Ac-IETD-CHO. Highest-resolution structure of a caspase reported to date. | [13] |
| Caspase-8 | 1QDU/2.80 Å | Bound to Z-EVD-dcmk. Additional interaction of Arg-177 with the Glu P3 residue. Stresses importance of S3 subsite for substrate recognition. | [12] |
| Caspase-8 | 1F9E/2.90 Å | Bound to Z-DEVD-CHO. Suggests important role of the S3 subsite in determining caspase specificity. | [65] |
| Caspase-8 | 1I4E/3.00 Å | Complex with baculovirus suicide inhibitor p35. Novel mechanism of proteinase inhibition. | [240] |
| Caspase-9 | 1JXQ/2.80 Å | Complex with Glu-Val-dehydrohymethyl aspartate. One active site occupied by inhibitor, the other free and distorted as in procaspase-7. | [73] |
| Caspase-9 | 1NW9/2.40 Å | Complex with XIAP (BIR3). Inhibitor blocks dimerization region of the (pro)caspase. | [122] |
| Caspase-1 | 1M72/2.30 Å | First structure of a non-human caspase (from Spodoptera frugiperda). Bound to Ac-DEV-Ask-methyl ketone. | [304] |
† S. J. Riedl, W. Bode, G. S. Salvesen and P. Fuentes-Prior, unpublished work.