6DEU

Human caspase-6 A109T

Summary for 6DEU

• Entry DOI: 10.2210/pdb6deu/pdb
• Descriptor: Caspase-6 (2 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 69062.52

Authors

Tubeleviciute-Aydin, A.,Beautrait, A.,Lynham, J.,Sharma, G.,Gorelik, A.,Deny, L.J.,Soya, N.,Lukacs, G.L.,Nagar, B.,Marinier, A.,LeBlanc, A.C. (deposition date: 2018-05-13, release date: 2019-03-27, Last modification date: 2023-10-11)

Primary citation

Tubeleviciute-Aydin, A.,Beautrait, A.,Lynham, J.,Sharma, G.,Gorelik, A.,Deny, L.J.,Soya, N.,Lukacs, G.L.,Nagar, B.,Marinier, A.,LeBlanc, A.C.
Identification of Allosteric Inhibitors against Active Caspase-6.
Sci Rep, 9:5504-5504, 2019

PubMed Abstract: Caspase-6 is a cysteine protease that plays essential roles in programmed cell death, axonal degeneration, and development. The excess neuronal activity of Caspase-6 is associated with Alzheimer disease neuropathology and age-dependent cognitive impairment. Caspase-6 inhibition is a promising strategy to stop early stage neurodegenerative events, yet finding potent and selective Caspase-6 inhibitors has been a challenging task due to the overlapping structural and functional similarities between caspase family members. Here, we investigated how four rare non-synonymous missense single-nucleotide polymorphisms (SNPs), resulting in amino acid substitutions outside human Caspase-6 active site, affect enzyme structure and catalytic efficiency. Three investigated SNPs were found to align with a putative allosteric pocket with low sequence conservation among human caspases. Virtual screening of 57,700 compounds against the putative Caspase-6 allosteric pocket, followed by in vitro testing of the best virtual hits in recombinant human Caspase-6 activity assays identified novel allosteric Caspase-6 inhibitors with IC and K values ranging from ~2 to 13 µM. This report may pave the way towards the development and optimisation of novel small molecule allosteric Caspase-6 inhibitors and illustrates that functional characterisation of rare natural variants holds promise for the identification of allosteric sites on other therapeutic targets in drug discovery.

PubMed: 30940883
DOI: 10.1038/s41598-019-41930-7

Experimental method

X-RAY DIFFRACTION (2.796 Å)