6CL0

Human caspase-3 in complex with Ac-ATS009-KE

Summary for 6CL0

• Entry DOI: 10.2210/pdb6cl0/pdb
• Related PRD ID: PRD_002450
• Descriptor: Caspase-3 subunit p17, Caspase-3 subunit p12, ACE-1MH-ASP-PF5-PHE-1U8, ... (4 entities in total)
• Functional Keywords: caspase-3, inhibitor, apoptosis, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 33693.97

Authors

Solania, A.T.,Gonzalez-Paez, G.E.,Wolan, D.W. (deposition date: 2018-03-01, release date: 2019-03-06, Last modification date: 2024-11-06)

Primary citation

Solania, A.,Gonzalez-Paez, G.E.,Wolan, D.W.
Selective and Rapid Cell-Permeable Inhibitor of Human Caspase-3.
Acs Chem.Biol., 14:2463-2470, 2019

PubMed Abstract: Individual roles and overlapping functionalities of 12 human caspases during apoptosis and other cellular processes remain poorly resolved primarily due to a lack of chemical tools. Here we present a new selective caspase-3 inhibitor, termed Ac-ATS010-KE, with rapid and irreversible binding kinetics. Relative to previously designed caspase-3-selective molecules that have tremendously abated inhibitory rates and thus limited use in biological settings, the improved kinetics of Ac-ATS010-KE permits its use in a cell-based capacity. We demonstrate that Ac-ATS010-KE prevents apoptosis with comparable efficacy to the general caspase inhibitor Ac-DEVD-KE and surprisingly does so without side-chain methylation. This observation is in contrast to the well-established peptide modification strategy typically employed for improving cellular permeability. Ac-ATS010-KE protects against extrinsic apoptosis, which demonstrates the utility of a thiophene carboxylate leaving group in biological settings, challenges the requisite neutralization of free carboxylic acids to improve cell permeability, and provides a tool-like compound to interrogate the role of caspase-3 in a variety of cellular processes.

PubMed: 31334631
DOI: 10.1021/acschembio.9b00564

Experimental method

X-RAY DIFFRACTION (1.5 Å)