7AAC

Crystal structure of the catalytic domain of human PARP1 in complex with veliparib

7AAC の概要

• エントリーDOI: 10.2210/pdb7aac/pdb
• 関連するPDBエントリー: 7AAA 7AAB 7AAD
• 分子名称: Poly [ADP-ribose] polymerase 1, (2R)-2-(7-carbamoyl-1H-benzimidazol-2-yl)-2-methylpyrrolidinium, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: parp inhibitor, parylation, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79306.58

構造登録者

Schimpl, M.,Ogden, T.E.H.,Yang, J.-C.,Easton, L.E.,Underwood, E.,Rawlins, P.B.,Johannes, J.W.,Embrey, K.J.,Neuhaus, D. (登録日: 2020-09-04, 公開日: 2021-01-13, 最終更新日: 2024-05-01)

主引用文献

Ogden, T.E.H.,Yang, J.C.,Schimpl, M.,Easton, L.E.,Underwood, E.,Rawlins, P.B.,McCauley, M.M.,Langelier, M.F.,Pascal, J.M.,Embrey, K.J.,Neuhaus, D.
Dynamics of the HD regulatory subdomain of PARP-1; substrate access and allostery in PARP activation and inhibition.
Nucleic Acids Res., 49:2266-2288, 2021

PubMed Abstract: PARP-1 is a key early responder to DNA damage in eukaryotic cells. An allosteric mechanism links initial sensing of DNA single-strand breaks by PARP-1's F1 and F2 domains via a process of further domain assembly to activation of the catalytic domain (CAT); synthesis and attachment of poly(ADP-ribose) (PAR) chains to protein sidechains then signals for assembly of DNA repair components. A key component in transmission of the allosteric signal is the HD subdomain of CAT, which alone bridges between the assembled DNA-binding domains and the active site in the ART subdomain of CAT. Here we present a study of isolated CAT domain from human PARP-1, using NMR-based dynamics experiments to analyse WT apo-protein as well as a set of inhibitor complexes (with veliparib, olaparib, talazoparib and EB-47) and point mutants (L713F, L765A and L765F), together with new crystal structures of the free CAT domain and inhibitor complexes. Variations in both dynamics and structures amongst these species point to a model for full-length PARP-1 activation where first DNA binding and then substrate interaction successively destabilise the folded structure of the HD subdomain to the point where its steric blockade of the active site is released and PAR synthesis can proceed.

PubMed: 33511412
DOI: 10.1093/nar/gkab020

実験手法

X-RAY DIFFRACTION (1.593 Å)