2HBR

Crystal structure of human caspase-1 (Arg286->Ala) in complex with 3-[2-(2-benzyloxycarbonylamino-3-methyl-butyrylamino)-propionylamino]-4-oxo-pentanoic acid (z-VAD-FMK)

Replaces:  2FQS

Summary for 2HBR

• Entry DOI: 10.2210/pdb2hbr/pdb
• Related: 1SC1 1SC3 1SC4 2FQQ 2HBQ 2HBY 2HBZ
• Related PRD ID: PRD_000338
• Descriptor: Caspase-1, N-[(benzyloxy)carbonyl]-L-valyl-N-[(2S)-1-carboxy-4-fluoro-3-oxobutan-2-yl]-L-alaninamide, ... (4 entities in total)
• Functional Keywords: active-site inhibitor, allosteric circuit, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P29466 P29466
• Total number of polymer chains: 3
• Total formula weight: 30514.39

Authors

Scheer, J.M.,Wells, J.A.,Romanowski, M.J. (deposition date: 2006-06-14, release date: 2006-06-27, Last modification date: 2024-10-30)

Primary citation

Scheer, J.M.,Romanowski, M.J.,Wells, J.A.
A Common Allosteric Site and Mechanism in Caspases
Proc.Natl.Acad.Sci.USA, 103:7595-7600, 2006

PubMed Abstract: We present a common allosteric mechanism for control of inflammatory and apoptotic caspases. Highly specific thiol-containing inhibitors of the human inflammatory caspase-1 were identified by using disulfide trapping, a method for site-directed small-molecule discovery. These compounds became trapped by forming a disulfide bond with a cysteine residue in the cavity at the dimer interface approximately 15 A away from the active site. Mutational and structural analysis uncovered a linear circuit of functional residues that runs from one active site through the allosteric cavity and into the second active site. Kinetic analysis revealed robust positive cooperativity not seen in other endopeptidases. Recently, disulfide trapping identified a similar small-molecule site and allosteric transition in the apoptotic caspase-7 that shares only a 23% sequence identity with caspase-1. Together, these studies show a general small-molecule-binding site for functionally reversing the zymogen activation of caspases and suggest a common regulatory site for the allosteric control of inflammation and apoptosis.

PubMed: 16682620
DOI: 10.1073/pnas.0602571103

Experimental method

X-RAY DIFFRACTION (2.2 Å)