3RJM

CASPASE2 IN COMPLEX WITH CHDI LIGAND 33c

Summary for 3RJM

• Entry DOI: 10.2210/pdb3rjm/pdb
• Related PRD ID: PRD_000786
• Descriptor: Caspase-2, Peptide inhibitor (ACE)VDV(3PX)D-CHO, ... (4 entities in total)
• Functional Keywords: caspase-2, p12, p19, caspase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 65885.56

Authors

Abendroth, J.,Lorimer, D.,Stewart, L.,Maillard, M.,Kiselyov, A.S. (deposition date: 2011-04-15, release date: 2011-09-21, Last modification date: 2023-12-06)

Primary citation

Maillard, M.C.,Brookfield, F.A.,Courtney, S.M.,Eustache, F.M.,Gemkow, M.J.,Handel, R.K.,Johnson, L.C.,Johnson, P.D.,Kerry, M.A.,Krieger, F.,Meniconi, M.,Munoz-Sanjuan, I.,Palfrey, J.J.,Park, H.,Schaertl, S.,Taylor, M.G.,Weddell, D.,Dominguez, C.
Exploiting differences in caspase-2 and -3 S(2) subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors.
Bioorg.Med.Chem., 19:5833-5851, 2011

PubMed Abstract: Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P(2) residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-l-proline along with four additional scaffold variants were selected as P(2) elements for their predicted ability to clash sterically with a residue of the caspase-3 S(2) pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and ∼200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.

PubMed: 21903398
DOI: 10.1016/j.bmc.2011.08.020

Experimental method

X-RAY DIFFRACTION (2.55 Å)