5DS3

Crystal structure of constitutively active PARP-1

Summary for 5DS3

• Entry DOI: 10.2210/pdb5ds3/pdb
• Descriptor: Poly [ADP-ribose] polymerase 1, PENTAETHYLENE GLYCOL, 4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)phthalazin-1(2H)-one, ... (5 entities in total)
• Functional Keywords: adp-ribosyl transferase, parp-1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 30868.14

Authors

Langelier, M.F.,Pascal, J.M. (deposition date: 2015-09-16, release date: 2016-07-27, Last modification date: 2024-10-16)

Primary citation

Dawicki-McKenna, J.M.,Langelier, M.F.,DeNizio, J.E.,Riccio, A.A.,Cao, C.D.,Karch, K.R.,McCauley, M.,Steffen, J.D.,Black, B.E.,Pascal, J.M.
PARP-1 Activation Requires Local Unfolding of an Autoinhibitory Domain.
Mol.Cell, 60:755-768, 2015

PubMed Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) creates the posttranslational modification PAR from substrate NAD(+) to regulate multiple cellular processes. DNA breaks sharply elevate PARP-1 catalytic activity to mount a cell survival repair response, whereas persistent PARP-1 hyperactivation during severe genotoxic stress is associated with cell death. The mechanism for tight control of the robust catalytic potential of PARP-1 remains unclear. By monitoring PARP-1 dynamics using hydrogen/deuterium exchange-mass spectrometry (HXMS), we unexpectedly find that a specific portion of the helical subdomain (HD) of the catalytic domain rapidly unfolds when PARP-1 encounters a DNA break. Together with biochemical and crystallographic analysis of HD deletion mutants, we show that the HD is an autoinhibitory domain that blocks productive NAD(+) binding. Our molecular model explains how PARP-1 DNA damage detection leads to local unfolding of the HD that relieves autoinhibition, and has important implications for the design of PARP inhibitors.

PubMed: 26626480
DOI: 10.1016/j.molcel.2015.10.013

Experimental method

X-RAY DIFFRACTION (2.6 Å)