PDBsum entry 3gjs

Apoptosis

PDB id: 3gjs

Contents

Protein chains

141 a.a. *

95 a.a. *

Ligands

ACE-TYR-VAL-ALA-ASJ ×2

Waters ×270

* Residue conservation analysis

PDB id:

3gjs

Name:

Apoptosis

Title:

Caspase-3 binds diverse p4 residues in peptides

Structure:

Caspase-3 subunit p17. Chain: a, c. Synonym: casp-3, apopain, cysteine protease cpp32, cpp-32, yama protein, srebp cleavage activity 1, sca-1, caspase-3 subunit p17, caspase-3 subunit p12. Engineered: yes. Caspase-3 subunit p12. Chain: b, d. Synonym: casp-3, apopain, cysteine protease cpp32, cpp-32, yama

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: casp3, cpp32. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes

Resolution:

1.90Å R-factor: 0.216 R-free: 0.248

Authors:

B.Fang,G.Fu,J.Agniswamy,R.W.Harrison,I.T.Weber

Key ref:

B.Fang et al. (2009). Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling. Apoptosis, 14, 741-752. PubMed id: 19283487

Date:

09-Mar-09 Release date: 24-Mar-09

Protein chains

P42574  (CASP3_HUMAN) -  Caspase-3 from Homo sapiens

Seq: 277 a.a.

Struc: 141 a.a.

Protein chains

P42574  (CASP3_HUMAN) -  Caspase-3 from Homo sapiens

Seq: 277 a.a.

Struc: 95 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.3.4.22.56 - caspase-3.

Apoptosis 14:741-752 (2009)

PubMed id: 19283487

Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling.

B.Fang, G.Fu, J.Agniswamy, R.W.Harrison, I.T.Weber.

ABSTRACT

Caspase-3 recognition of various P4 residues in its numerous protein substrates was investigated by crystallography, kinetics, and calculations on model complexes. Asp is the most frequent P4 residue in peptide substrates, although a wide variety of P4 residues are found in the cellular proteins cleaved by caspase-3. The binding of peptidic inhibitors with hydrophobic P4 residues, or no P4 residue, is illustrated by crystal structures of caspase-3 complexes with Ac-IEPD-Cho, Ac-WEHD-Cho, Ac-YVAD-Cho, and Boc-D(OMe)-Fmk at resolutions of 1.9-2.6 A. The P4 residues formed favorable hydrophobic interactions in two separate hydrophobic regions of the binding site. The side chains of P4 Ile and Tyr form hydrophobic interactions with caspase-3 residues Trp206 and Trp214 within a non-polar pocket of the S4 subsite, while P4 Trp interacts with Phe250 and Phe252 that can also form the S5 subsite. These interactions of hydrophobic P4 residues are distinct from those for polar P4 Asp, which indicates the adaptability of caspase-3 for binding diverse P4 residues. The predicted trends in peptide binding from molecular models had high correlation with experimental values for peptide inhibitors. Analysis of structural models for the binding of 20 different amino acids at P4 in the aldehyde peptide Ac-XEVD-Cho suggested that the majority of hydrophilic P4 residues interact with Phe250, while hydrophobic residues interact with Trp206, Phe250, and Trp214. Overall, the S4 pocket of caspase-3 exhibits flexible adaptation for different residues and the new structures and models, especially for hydrophobic P4 residues, will be helpful for the design of caspase-3 based drugs.