5O2D

PARP14 Macrodomain 2 with inhibitor

5O2D の概要

• エントリーDOI: 10.2210/pdb5o2d/pdb
• 分子名称: Poly [ADP-ribose] polymerase 14, ~{N}-[2-(9~{H}-carbazol-1-yl)phenyl]methanesulfonamide (3 entities in total)
• 機能のキーワード: parp, adp-ribose, structural genomics, structural genomics consortium, sgc, adp-ribose-binding-protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 21929.90

構造登録者

Uth, K.,Schuller, M.,Sieg, C.,Wang, J.,Krojer, T.,Knapp, S.,Riedels, K.,Bracher, F.,Edwards, A.M.,Arrowsmith, C.,Bountra, C.,Elkins, J.M.,Structural Genomics Consortium (SGC) (登録日: 2017-05-20, 公開日: 2017-11-08, 最終更新日: 2024-05-08)

主引用文献

Schuller, M.,Riedel, K.,Gibbs-Seymour, I.,Uth, K.,Sieg, C.,Gehring, A.P.,Ahel, I.,Bracher, F.,Kessler, B.M.,Elkins, J.M.,Knapp, S.
Discovery of a Selective Allosteric Inhibitor Targeting Macrodomain 2 of Polyadenosine-Diphosphate-Ribose Polymerase 14.
ACS Chem. Biol., 12:2866-2874, 2017

PubMed Abstract: Macrodomains are conserved protein interaction modules that can be found in all domains of life including in certain viruses. Macrodomains mediate recognition of sequence motifs harboring adenosine diphosphate ribose (ADPR) modifications, thereby regulating a variety of cellular processes. Due to their role in cancer or viral pathogenesis, macrodomains have emerged as potential therapeutic targets, but the unavailability of small molecule inhibitors has hampered target validation studies so far. Here, we describe an efficient screening strategy for identification of small molecule inhibitors that displace ADPR from macrodomains. We report the discovery and characterization of a macrodomain inhibitor, GeA-69, selectively targeting macrodomain 2 (MD2) of PARP14 with low micromolar affinity. Co-crystallization of a GeA-69 analogue with PARP14 MD2 revealed an allosteric binding mechanism explaining its selectivity over other human macrodomains. We show that GeA-69 engages PARP14 MD2 in intact cells and prevents its localization to sites of DNA damage.

PubMed: 28991428
DOI: 10.1021/acschembio.7b00445

実験手法

X-RAY DIFFRACTION (1.6 Å)