3GJT

Caspase-3 Binds Diverse P4 Residues in Peptides

3GJT の概要

• エントリーDOI: 10.2210/pdb3gjt/pdb
• 関連するPDBエントリー: 3GJQ 3GJR 3GJS
• 分子名称: Caspase-3 subunit p17, Caspase-3 subunit p12, peptide inhibitor, ... (4 entities in total)
• 機能のキーワード: enzyme catalysis, cysteine protease, protein recognition, apoptosis, cytoplasm, hydrolase, phosphoprotein, polymorphism, protease, s-nitrosylation, thiol protease, zymogen
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: P42574 P42574
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 59755.83

構造登録者

Fang, B.,Fu, G.,Agniswamy, J.,Harrison, R.W.,Weber, I.T. (登録日: 2009-03-09, 公開日: 2009-03-24, 最終更新日: 2024-11-06)

主引用文献

Fang, B.,Fu, G.,Agniswamy, J.,Harrison, R.W.,Weber, I.T.
Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling.
Apoptosis, 14:741-752, 2009

PubMed 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.

PubMed: 19283487
DOI: 10.1007/s10495-009-0333-y

実験手法

X-RAY DIFFRACTION (2.2 Å)