PDBsum entry 1sc3

Hydrolase

PDB id: 1sc3

Contents

Protein chains

173 a.a. *

88 a.a. *

Ligands

MLI

Waters ×276

* Residue conservation analysis

PDB id:

1sc3

Name:

Hydrolase

Title:

Crystal structure of the human caspase-1 c285a mutant in complex with malonate

Structure:

Interleukin-1 beta convertase. Chain: a. Fragment: interleukin-1 beta convertase p20. Synonym: il-1bc, il-1 beta converting enzyme, ice, interleukin-1 beta converting enzyme, p45, caspase-1, casp-1. Engineered: yes. Mutation: yes. Interleukin-1 beta convertase. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: casp1, il1bc, il1bce. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PDB file)

Resolution:

1.80Å R-factor: 0.207 R-free: 0.238

Authors:

M.J.Romanowski,J.M.Scheer,T.O'Brien,R.S.Mcdowell

Key ref:

M.J.Romanowski et al. (2004). Crystal structures of a ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding. Structure, 12, 1361-1371. PubMed id: 15296730 DOI: 10.1016/j.str.2004.05.010

Date:

11-Feb-04 Release date: 10-Aug-04

Protein chain

P29466  (CASP1_HUMAN) -  Caspase-1 from Homo sapiens

Seq: 404 a.a.

Struc: 173 a.a.*

Protein chain

P29466  (CASP1_HUMAN) -  Caspase-1 from Homo sapiens

Seq: 404 a.a.

Struc: 88 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.22.36 - caspase-1.
• Reaction: Release of interleukin 1-beta by specific cleavage at 116-Asp-|-Ala-117 and 27-Asp-|-Gly-28 bonds in precursor. Also hydrolyzes the small- molecule substrate, Ac-Tyr-Val-Ala-Asp-|-NHMec.

DOI no: 10.1016/j.str.2004.05.010

Structure 12:1361-1371 (2004)

PubMed id: 15296730

Crystal structures of a ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding.

M.J.Romanowski, J.M.Scheer, T.O'Brien, R.S.McDowell.

ABSTRACT

Caspase-1, a mediator of the posttranslational processing of IL-1beta and IL-18, requires an aspartic acid in the P1 position of its substrates. The mechanisms of caspase-1 activation remain poorly understood despite numerous structures of the enzyme complexed with aspartate-based inhibitors. Here we report a crystal structure of ligand-free caspase-1 that displays dramatic rearrangements of loops defining the active site to generate a closed conformation that is incompatible with substrate binding. A structure of the enzyme complexed with malonate shows the protein in its open (active-site ligand-bound) conformation in which malonate reproduces the hydrogen bonding network observed in structures with covalent inhibitors. These results illustrate the essential function of the obligatory aspartate recognition element that opens the active site of caspase-1 to substrates and may be the determinant responsible for the conformational changes between ligand-free and -bound forms of the enzyme, and suggest a new approach for identifying novel aspartic acid mimetics.

Selected figure(s)

Figure 3.
Figure 3. The Central Cavity at the Dimer-Dimer Interface in Human Caspase-1The active site is indicated by orange ellipses; the dimer-dimer interface is enclosed by a yellow box.(A) Surface representation of the residues surrounding the closed cavity in the enzyme complexed with an active-site inhibitor.(B) Surface representation of the residues surrounding the open cavity in the active-site ligand-free enzyme.

The above figure is reprinted by permission from Cell Press: Structure (2004, 12, 1361-1371) copyright 2004.

Figure was selected by an automated process.