2P2C

Inhibition of caspase-2 by a designed ankyrin repeat protein (DARPin)

Summary for 2P2C

• Entry DOI: 10.2210/pdb2p2c/pdb
• Related: 1MJO 1PYO
• Descriptor: Caspase-2, ... (4 entities in total)
• Functional Keywords: apoptosis, caspase, caspase-2, inhibition, protein design, protein libraries, designed ankyrin repeat proteins, ribosome display, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 18
• Total formula weight: 297019.76

Authors

Roschitzki Voser, H.,Briand, C.,Capitani, G.,Gruetter, M.G. (deposition date: 2007-03-07, release date: 2007-05-22, Last modification date: 2024-10-16)

Primary citation

Schweizer, A.,Roschitzki-Voser, H.,Amstutz, P.,Briand, C.,Gulotti-Georgieva, M.,Prenosil, E.,Binz, H.K.,Capitani, G.,Baici, A.,Pluckthun, A.,Grutter, M.G.
Inhibition of Caspase-2 by a Designed Ankyrin Repeat Protein: Specificity, Structure, and Inhibition Mechanism.
Structure, 15:625-636, 2007

PubMed Abstract: Specific and potent caspase inhibitors are indispensable for the dissection of the intricate pathways leading to apoptosis. We selected a designed ankyrin repeat protein (DARPin) from a combinatorial library that inhibits caspase-2 in vitro with a subnanomolar inhibition constant and, in contrast to the peptidic caspase inhibitors, with very high specificity for this particular caspase. The crystal structure of this inhibitor (AR_F8) in complex with caspase-2 reveals the molecular basis for the specificity and, together with kinetic analyses, the allosteric mechanism of inhibition. The structure also shows a conformation of the active site that can be exploited for the design of inhibitory compounds. AR_F8 is a specific inhibitor of an initiator caspase and has the potential to help identify the function of caspase-2 in the complex biological apoptotic signaling network.

PubMed: 17502107
DOI: 10.1016/j.str.2007.03.014

Experimental method

X-RAY DIFFRACTION (3.24 Å)