7RNG

Crystal structure of caspase-3 with inhibitor Ac-ITAKD-CHO

Summary for 7RNG

• Entry DOI: 10.2210/pdb7rng/pdb
• Descriptor: Caspase-3 subunit p17, Caspase-3 subunit p12, Ac-ITAKD-CHO, ... (4 entities in total)
• Functional Keywords: hydrolase/hydrolase inhibitor, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 55765.80

Authors

McCue, W.,Finzel, B.C. (deposition date: 2021-07-29, release date: 2022-06-01, Last modification date: 2024-02-07)

Primary citation

Bresinsky, M.,Strasser, J.M.,Hubmann, A.,Vallaster, B.,McCue, W.M.,Fuller, J.,Singh, G.,Nelson, K.M.,Cuellar, M.E.,Finzel, B.C.,Ashe, K.H.,Walters, M.A.,Pockes, S.
Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis.
Arch Pharm, 355:e2200095-e2200095, 2022

PubMed Abstract: Since the discovery of the caspase-2 (Casp2)-mediated ∆tau314 cleavage product and its associated impact on tauopathies such as Alzheimer's disease, the design of selective Casp2 inhibitors has become a focus in medicinal chemistry research. In the search for new lead structures with respect to Casp2 selectivity and drug-likeness, we have taken an approach by looking more closely at the specific sites of Casp2-mediated proteolysis. Using seven selected protein cleavage sequences, we synthesized a peptide series of 53 novel molecules and studied them using in vitro pharmacology, molecular modeling, and crystallography. Regarding Casp2 selectivity, AcITV(Dab)D-CHO (23) and AcITV(Dap)D-CHO (26) demonstrated the best selectivity (1-6-fold), although these trends were only moderate. However, some analogous tetrapeptides, most notably AcDKVD-CHO (45), showed significantly increased Casp3 selectivities (>100-fold). Tetra- and tripeptides display decreased or no Casp2 affinity, supporting the assumption that a motif of five amino acids is required for efficient Casp2 inhibition. Overall, the results provide a reasonable basis for the development of both selective Casp2 and Casp3 inhibitors.

PubMed: 35642311
DOI: 10.1002/ardp.202200095

Experimental method

X-RAY DIFFRACTION (2.55 Å)