4N7J

Tailoring Small Molecules for an Allosteric Site on Procaspase-6

Summary for 4N7J

• Entry DOI: 10.2210/pdb4n7j/pdb
• Related: 4N5D 4N6G 4N7M 4NBK 4NBL 4NBN
• Descriptor: Caspase-6, PHOSPHATE ION, 3-(pyrrolidin-1-yl)isoquinolin-1(2H)-one, ... (4 entities in total)
• Functional Keywords: procaspse-6, caspase-6 zymogen, allosteric, structure based drug design, caspase, cysteine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P55212
• Total number of polymer chains: 2
• Total formula weight: 65316.83

Authors

Murray, J.M.,Steffek, M. (deposition date: 2013-10-15, release date: 2013-12-18, Last modification date: 2024-02-28)

Primary citation

Murray, J.,Giannetti, A.M.,Steffek, M.,Gibbons, P.,Hearn, B.R.,Cohen, F.,Tam, C.,Pozniak, C.,Bravo, B.,Lewcock, J.,Jaishankar, P.,Ly, C.Q.,Zhao, X.,Tang, Y.,Chugha, P.,Arkin, M.R.,Flygare, J.,Renslo, A.R.
Tailoring small molecules for an allosteric site on procaspase-6.
Chemmedchem, 9:73-77, 2014

PubMed Abstract: Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting the active site. Allosteric modulation of caspase activity is an alternate strategy that potentially avoids the need for anionic and electrophilic functionality present in most active-site inhibitors. Caspase-6 has been implicated in neurodegenerative disease, including Huntington's and Alzheimer's diseases. Herein we describe a fragment-based lead discovery effort focused on caspase-6 in its active and zymogen forms. Fragments were identified for procaspase-6 using surface plasmon resonance methods and subsequently shown by X-ray crystallography to bind a putative allosteric site at the dimer interface. A fragment-merging strategy was employed to produce nanomolar-affinity ligands that contact residues in the L2 loop at the dimer interface, significantly stabilizing procaspase-6. Because rearrangement of the L2 loop is required for caspase-6 activation, our results suggest a strategy for the allosteric control of caspase activation with drug-like small molecules.

PubMed: 24259468
DOI: 10.1002/cmdc.201300424

Experimental method

X-RAY DIFFRACTION (1.673 Å)