4C9W

Crystal structure of NUDT1 (MTH1) with R-crizotinib

4C9W の概要

• エントリーDOI: 10.2210/pdb4c9w/pdb
• 関連するPDBエントリー: 4C9X
• 分子名称: 7,8-DIHYDRO-8-OXOGUANINE TRIPHOSPHATASE, CHLORIDE ION, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-amine, ... (5 entities in total)
• 機能のキーワード: hydrolase, crizotinib
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform p18: Cytoplasm. Isoform p26: Cytoplasm: P36639
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19065.69

構造登録者

Elkins, J.M.,Salah, E.,Huber, K.,Superti-Furga, G.,Abdul Azeez, K.R.,Raynor, J.,Krojer, T.,von Delft, F.,Bountra, C.,Edwards, A.,Knapp, S. (登録日: 2013-10-03, 公開日: 2014-04-02, 最終更新日: 2023-12-20)

主引用文献

Huber, K.V.M.,Salah, E.,Radic, B.,Gridling, M.,Elkins, J.M.,Stukalov, A.,Jemth, A.,Gokturk, C.,Sanjiv, K.,Stromberg, K.,Pham, T.,Berglund, U.W.,Colinge, J.,Bennett, K.L.,Loizou, J.I.,Helleday, T.,Knapp, S.,Superti-Furga, G.
Stereospecific Targeting of Mth1 by (S)-Crizotinib as an Anticancer Strategy.
Nature, 508:222-, 2014

PubMed Abstract: Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.

PubMed: 24695225
DOI: 10.1038/NATURE13194

実験手法

X-RAY DIFFRACTION (1.65 Å)