02 May 2003
A mechanism for PARP-1 activation based on modeling studies of a ‘gain of function’ mutation
C. Patel, M. OliveiraMed Sci Monit 2003; 9(1): 54-0 :: ID: 15118
Abstract
PARP-1 is 113kDa natural biosensor whose activity increases 500 fold upon recognition of single strand break recognition. DNA binding by the N-terminal zinc finger domains triggers activation of the ADP-Ribose polymerization at the C-terminal end. Current PARP-1 inhibitors target a highly conserved nicotinamide pocket found in ADP-Ribosyl transferase (ADPRT) domain, which is present in all the members of the PARP family, thus they lack selectivity. Therapeutic benefits for PARP-1 inhibitors have only been shown in the selective PARP-1 knockout mouse. We have decided to investigate the allosteric activation of PARP-1 as a tool in the design of selective inhibitors. For this purpose we have focused on understanding the structural basis for a PARP-1 ‘gain of function’ mutation, L713F, which is reported to increase kcat/KM by ~9 fold. We have used the program InsightII to model human PARP-1, based on the known structure of the chicken catalytic fragment of PARP-1 (CF-PARP-1) and generated a model for L713F. The structure was energy minimized and molecular dynamics was utilized as a tool to investigate the flexibility of this two domain structure. The position L713F is found in the fourth helix of the all alpha helix domain of CF-PARP-1 ~3.0A away from the interface with the ADPRT domain. The structural changes due to the mutation are confined to a 4A radius of the mutation site. Our analysis suggests a mechanism for activation.References: 1.Alvez-Miranda, Dantzer F, O’Farrel M, de Murcia G, Menissier-de Murcia: Biochem Biophys Res Commun, 212, 317-325
Keywords: poly(ADP-ribose) polymerase-1, PARP-1, activation mechanism
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