5DSY

Crystal structure of constitutively active PARP-2

Summary for 5DSY

• Entry DOI: 10.2210/pdb5dsy/pdb
• Descriptor: Poly [ADP-ribose] polymerase 2, 2-[4-[(2S,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]carbonylpiperazin-1-yl]-N-(1-oxidanylidene-2,3-dihydroisoindol-4-yl)ethanamide (3 entities in total)
• Functional Keywords: adp-ribosyl transferase, parp, parp-2, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 128853.78

Authors

Riccio, A.A.,Pascal, J.M. (deposition date: 2015-09-17, release date: 2016-07-27, Last modification date: 2023-09-27)

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 (2.7 Å)