Abstract
Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptional regulation, and is targeted by a number of clinical inhibitors. Despite this, catalytic mechanism of PARP1 remains largely underexplored because of the complex substrate/product structure. Using molecular modeling and metadynamics simulations we have described in detail elongation of poly(ADP-ribose) chain in the PARP1 active site. It was shown that elongation reaction proceeds via the SN1-like mechanism involving formation of the intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2′A-OH group of the acceptor substrate can be activated by the general base Glu988 not directly but through the proton relay system including the adjacent 3′A-OH group.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
