Open AccessStructural basis for allosteric PARP-1 retention on DNA breaks
Author(s) -
Levani Zandarashvili,
Marie-France Langelier,
Uday Kiran Velagapudi,
Mark A. Hancock,
Jamin D. Steffen,
Ramya Billur,
Zain M. Hannan,
Andrew J. Wicks,
Dragomir B. Krastev,
Stephen J. Pettitt,
Christopher J. Lord,
Tanaji T. Talele,
John M. Pascal,
Ben E. Black
Publication year - 2020
Publication title -
science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 12.556
H-Index - 1186
eISSN - 1095-9203
pISSN - 0036-8075
DOI - 10.1126/science.aax6367
Subject(s) - poly adp ribose polymerase , allosteric regulation , dna , dna repair , polymerase , chemistry , dna damage , parp inhibitor , computational biology , cancer research , biochemistry , biology , enzyme
DNA death grip Poly(ADP-ribose) polymerase–1 (PARP-1) binds to DNA breaks and recruits DNA repair components. Cancer-killing PARP-1 inhibitor (PARPi) compounds all block the same catalytic site but exhibit vastly different efficacy. Zandarashviliet al. investigated the molecular impact of PARPi binding to PARP-1 (see the Perspective by Slade and Eustermann). Different PARPi molecules perturb PARP-1 allostery in diverse manners: Some drive allostery to promote release of PARP-1 from DNA, and others drive allostery to promote retention. These insights help explain the different efficacies in the clinic and enable conversion of a pro-release, ineffective cancer-killing compound to a pro-retention, more effective PARPi.Science , this issue p.eaax6367 ; see also p.30
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