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|2h51, resolution 2.10Å ()|
|Gene:||CASP1, IL1BC, IL1BCE (Homo sapiens)|
|Related:||2fqv, 1sc3, 2fqq, 2fqr, 2fqs, 2fqu, 2h48, 2h44, 2h4w, 2h54|
Crystal structure of human caspase-1 (Glu390->Asp and Arg286->Lys) in complex with 3-[2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-propionylamino]-4-oxo-pentanoic acid (z-VAD-FMK)
Structural studies of caspase-1 reveal that the dimeric thiol protease can exist in two states: in an on-state, when the active site is occupied, or in an off-state, when the active site is empty or when the enzyme is bound by a synthetic allosteric ligand at the dimer interface approximately 15 A from the active site. A network of 21 hydrogen bonds from nine side chains connecting the active and allosteric sites change partners when going between the on-state and the off-state. Alanine-scanning mutagenesis of these nine side chains shows that only two of them-Arg286 and Glu390, which form a salt bridge-have major effects, causing 100- to 200-fold reductions in catalytic efficiency (k(cat)/K(m)). Two neighbors, Ser332 and Ser339, have minor effects, causing 4- to 7-fold reductions. A more detailed mutational analysis reveals that the enzyme is especially sensitive to substitutions of the salt bridge: even a homologous R286K substitution causes a 150-fold reduction in k(cat)/K(m). X-ray crystal structures of these variants suggest the importance of both the salt bridge interaction and the coordination of solvent water molecules near the allosteric binding pocket. Thus, only a small subset of side chains from the larger hydrogen bonding network is critical for activity. These form a contiguous set of interactions that run from one active site through the allosteric site at the dimer interface and onto the second active site. This subset constitutes a functional allosteric circuit or "hot wire" that promotes site-to-site coupling.
An allosteric circuit in caspase-1., Datta D, Scheer JM, Romanowski MJ, Wells JA, J Mol Biol. 2008 Sep 19;381(5):1157-67. Epub 2008 Jun 20. PMID:18590738
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Datta D, Scheer JM, Romanowski MJ, Wells JA. An allosteric circuit in caspase-1. J Mol Biol. 2008 Sep 19;381(5):1157-67. Epub 2008 Jun 20. PMID:18590738 doi:10.1016/j.jmb.2008.06.040
- Fang B, Boross PI, Tozser J, Weber IT. Structural and kinetic analysis of caspase-3 reveals role for s5 binding site in substrate recognition. J Mol Biol. 2006 Jul 14;360(3):654-66. Epub 2006 Jun 2. PMID:16781734 doi:10.1016/j.jmb.2006.05.041