Structural basis for allosteric PARP-1 retention on DNA breaks
| Autor: | Marie-France Langelier, Ben E. Black, Levani Zandarashvili, Jamin D. Steffen, Andrew J. Wicks, John M. Pascal, Uday Kiran Velagapudi, Tanaji T. Talele, Stephen J. Pettitt, Ramya Billur, Christopher J. Lord, Mark A. Hancock, Zain M. Hannan, Dragomir B. Krastev |
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| Rok vydání: | 2019 |
| Předmět: |
Poly ADP ribose polymerase
Allosteric regulation Protein domain Poly (ADP-Ribose) Polymerase-1 Isoindoles Poly(ADP-ribose) Polymerase Inhibitors Piperazines Article 03 medical and health sciences 0302 clinical medicine Allosteric Regulation Protein Domains Cell Line Tumor Neoplasms Humans A-DNA 030304 developmental biology chemistry.chemical_classification 0303 health sciences Multidisciplinary Extramural DNA Breaks 3. Good health Enzyme chemistry 030220 oncology & carcinogenesis Dna breaks Cancer cell Biophysics Benzimidazoles DNA Damage |
| Zdroj: | Science |
| ISSN: | 1095-9203 |
| Popis: | 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. Zandarashvili et 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 |
| Databáze: | OpenAIRE |
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