8VP4

Crystal Structure of JF1cpCasp2 with Peptide Inhibitor AcVDVAD-CHO

8VP4 の概要

• エントリーDOI: 10.2210/pdb8vp4/pdb
• 関連するBIRD辞書のPRD_ID: PRD_001048
• 分子名称: JF1cpCasp2, AcVDVAD-CHO (3 entities in total)
• 機能のキーワード: caspase-2, inhibitor, alzheimer's disease, dimer, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 64465.56

構造登録者

Fuller, J.L.,Shi, K.,Walters, M.A.,Finzel, B.C. (登録日: 2024-01-16, 公開日: 2025-04-09)

主引用文献

Fuller, J.L.,Shi, K.,Pockes, S.,Finzel, B.C.,Ashe, K.H.,Walters, M.A.
Reengineering of Circularly Permuted Caspase-2 to Enhance Enzyme Stability and Enable Crystallographic Studies.
Acs Chem.Biol., 2025

PubMed Abstract: Caspase activation has been linked to several diseases, including cancer, neurodegeneration, and inflammatory conditions, generating interest in targeting this family of proteases for drug development. Caspase-2 (Casp2) in particular has been implicated in Alzheimer's Disease (AD) by cleaving tau protein into fragment Δtau314, which reversibly impairs cognitive and synaptic function. Thus, Casp2 inhibition could be a useful strategy for therapeutic treatment of AD. To that end, we have previously synthesized and characterized various series of peptide and peptidomimetic inhibitors that demonstrate potency and selectivity for Casp2 over caspase-3 (Casp3). Despite promising developments in the design of selective Casp2 inhibitors, low expression yields of Casp2 hinder crystallographic experiments and make structure-based design challenging. The design of circularly permuted (cp) Casp2 increased protein yields considerably; however, this protein could not be crystallized. This article describes the characterization of ten novel cpCasp2 mutants, designed with the goal of increasing stability and facilitating crystallization. Gratifyingly, engineered mutant JF1cpCasp2 displayed high relative stability and was readily crystallizable with the canonical Casp2 inhibitor AcVDVAD-CHO, leading to what we believe to be the first crystal structures of any reverse caspase in the PDB. Moreover, we have reported the structure of JF1cpCasp2 with our recently described Casp2-selective inhibitor MUR-65, which revealed a unique interaction with Arg417 in the binding pocket. Overall, JF1cpCasp2 has proven valuable for structure-based design and expanding understanding of Casp2 inhibition, with potential implications for drug discovery and the development of more selective compounds.

PubMed: 40117490
DOI: 10.1021/acschembio.4c00795

実験手法

X-RAY DIFFRACTION (1.51 Å)