8RDZ

Crystal Structure of Human ADP-ribose Pyrophosphatase NUDT5 In complex with Ibrutinib

これはPDB形式変換不可エントリーです。

8RDZ の概要

• エントリーDOI: 10.2210/pdb8rdz/pdb
• 分子名称: ADP-sugar pyrophosphatase, MAGNESIUM ION, Ibrutinib (unbound form), ... (5 entities in total)
• 機能のキーワード: nudix domain, adpr, adp-ribose pyrophosphatase, nudt5, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 99813.29

構造登録者

Raux, B.,Huber, K.V.M. (登録日: 2023-12-09, 公開日: 2024-05-01, 最終更新日: 2024-05-22)

主引用文献

Balikci, E.,Marques, A.M.C.,Bauer, L.G.,Seupel, R.,Bennett, J.,Raux, B.,Buchan, K.,Simelis, K.,Singh, U.,Rogers, C.,Ward, J.,Cheng, C.,Szommer, T.,Schutzenhofer, K.,Elkins, J.M.,Sloman, D.L.,Ahel, I.,Fedorov, O.,Brennan, P.E.,Huber, K.V.M.
Unexpected Noncovalent Off-Target Activity of Clinical BTK Inhibitors Leads to Discovery of a Dual NUDT5/14 Antagonist.
J.Med.Chem., 67:7245-7259, 2024

PubMed Abstract: Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead. Further investigation of the prototypical BTK inhibitor ibrutinib also revealed potent inhibition of the largely unstudied NUDIX hydrolase family member NUDT14. By exploring structure-activity relationships (SARs) around the core scaffold, we identify a potent, noncovalent, and cell-active dual NUDT5/14 inhibitor. Cocrystallization experiments yielded new insights into the NUDT14 hydrolase active site architecture and inhibitor binding, thus providing a basis for future chemical probe design.

PubMed: 38635563
DOI: 10.1021/acs.jmedchem.4c00072

実験手法

X-RAY DIFFRACTION (2.02 Å)