2Y0B

Caspase-3 in Complex with an Inhibitory DARPin-3.4_S76R

Summary for 2Y0B

• Entry DOI: 10.2210/pdb2y0b/pdb
• Related: 1CP3 1GFW 1I3O 1NME 1NMQ 1NMS 1PAU 1QX3 1RE1 1RHJ 1RHK 1RHM 1RHQ 1RHR 1RHU 2C1E 2C2K 2C2M 2C2O 2CDR 2CJX 2CJY 2CNK 2CNL 2CNN 2CNO 2DKO 2J30 2J31 2J32 2J33 2XYG 2XYH 2XYP 2XZD 2XZT
• Descriptor: CASPASE-3 SUBUNIT P17, CASPASE-3, DARPIN-3.4_S76R, ... (6 entities in total)
• Functional Keywords: hydrolase-protein binding complex, structure-activity relationship, ankyrin repeat protein, ribosome display, apoptosis, hydrolase/protein binding
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 6
• Total formula weight: 91507.80

Authors

Barandun, J.,Schroeder, T.,Mittl, P.,Grutter, M.G. (deposition date: 2010-12-01, release date: 2011-12-21, Last modification date: 2024-11-06)

Primary citation

Schroeder, T.,Barandun, J.,Flutsch, A.,Briand, C.,Mittl, P.,Grutter, M.G.
Specific Inhibition of Caspase-3 by a Competitive Darpin: Molecular Mimicry between Native and Designed Inhibitors.
Structure, 21:277-, 2013

PubMed Abstract: Dysregulation of apoptosis is associated with several human diseases. The main apoptotic mediators are caspases, which propagate death signals to downstream targets. Executioner caspase-3 is responsible for the majority of cleavage events and its therapeutic potential is of high interest with to date several available active site peptide inhibitors. These molecules inhibit caspase-3, but also homologous caspases. Here, we describe caspase-3 specific inhibitors D3.4 and D3.8, which have been selected from a library of designed ankyrin repeat proteins (DARPins). The crystal structures of D3.4 and mutants thereof show how high specificity and inhibition is achieved. They also show similarities in the binding mode with that of the natural caspase inhibitor XIAP (X-linked inhibitor of apoptosis). The kinetic data reveal a competitive inhibition mechanism. D3.4 is specific for caspase-3 and does not bind the highly homologous caspase-7. D3.4 therefore is an excellent tool to define the precise role of caspase-3 in the various apoptotic pathways.

PubMed: 23333429
DOI: 10.1016/J.STR.2012.12.011

Experimental method

X-RAY DIFFRACTION (2.1 Å)