6BHV

Human PARP-1 bound to NAD+ analog benzamide adenine dinucleotide (BAD)

Summary for 6BHV

• Entry DOI: 10.2210/pdb6bhv/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) (3 entities in total)
• Functional Keywords: parp-1, artd1, poly(adp-ribose) polymerase, non-hydrolyzable nad+ analog, parp, adp-ribose, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 122662.85

Authors

Pascal, J.M.,Langelier, M.F. (deposition date: 2017-10-31, release date: 2018-02-28, Last modification date: 2023-10-04)

Primary citation

Langelier, M.F.,Zandarashvili, L.,Aguiar, P.M.,Black, B.E.,Pascal, J.M.
NAD+analog reveals PARP-1 substrate-blocking mechanism and allosteric communication from catalytic center to DNA-binding domains.
Nat Commun, 9:844-844, 2018

PubMed Abstract: PARP-1 cleaves NAD and transfers the resulting ADP-ribose moiety onto target proteins and onto subsequent polymers of ADP-ribose. An allosteric network connects PARP-1 multi-domain detection of DNA damage to catalytic domain structural changes that relieve catalytic autoinhibition; however, the mechanism of autoinhibition is undefined. Here, we show using the non-hydrolyzable NAD analog benzamide adenine dinucleotide (BAD) that PARP-1 autoinhibition results from a selective block on NAD binding. Following DNA damage detection, BAD binding to the catalytic domain leads to changes in PARP-1 dynamics at distant DNA-binding surfaces, resulting in increased affinity for DNA damage, and providing direct evidence of reverse allostery. Our findings reveal a two-step mechanism to activate and to then stabilize PARP-1 on a DNA break, indicate that PARP-1 allostery influences persistence on DNA damage, and have important implications for PARP inhibitors that engage the NAD binding site.

PubMed: 29487285
DOI: 10.1038/s41467-018-03234-8

Experimental method

X-RAY DIFFRACTION (2.3 Å)