9BPY

Human PARP1 ART domain bound to NAD+ analogs benzamide adenine dinucleotide and carba-NAD+

Summary for 9BPY

• Entry DOI: 10.2210/pdb9bpy/pdb
• Descriptor: Poly [ADP-ribose] polymerase 1, [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl [(2R,3S,4R,5S)-5-(3-carbamoylphenyl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl dihydrogen diphosphate (non-preferred name), CARBA-NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• Functional Keywords: parp1, nad+ analog, adp-ribosyl transferase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 123325.31

Authors

Langelier, M.F.,Pascal, J.M. (deposition date: 2024-05-08, release date: 2025-02-05)

Primary citation

Langelier, M.F.,Mirhasan, M.,Gilbert, K.,Sverzhinksy, A.,Furtos, A.,Pascal, J.M.
PARP enzyme de novo synthesis of protein-free poly(ADP-ribose).
Mol.Cell, 84:4758-4773.e6, 2024

PubMed Abstract: PARP enzymes transfer ADP-ribose from NAD onto proteins as a covalent modification that regulates multiple aspects of cell biology. Here, we identify an undiscovered catalytic activity for human PARP1: de novo generation of free PAR molecules that are not attached to proteins. Free PAR production arises when a molecule of NAD or ADP-ribose docks in the PARP1 acceptor site and attaches to an NAD molecule bound to the donor site, releasing nicotinamide and initiating ADP-ribose chains that emanate from NAD/ADP-ribose rather than protein. Free PAR is also produced by human PARP2 and the PARP enzyme Tankyrase. We demonstrate that free PAR in cells is generated mostly by PARP1 de novo synthesis activity rather than by PAR-degrading enzymes PAR glycohydrolase (PARG), ARH3, and TARG1 releasing PAR from protein. The coincident production of free PAR and protein-linked modifications alters models for PAR signaling and broadens the scope of PARP enzyme signaling capacity.

PubMed: 39536748
DOI: 10.1016/j.molcel.2024.10.024

Experimental method

X-RAY DIFFRACTION (2.8 Å)