Probing the KRas Switch II Groove by Fluorine NMR Spectroscopy

Autor:	Mark John Kelly, David Peacock, Kevan Shokat
Rok vydání:	2022
Předmět:	Proto-Oncogene Proteins p21(ras) Genes ras Magnetic Resonance Spectroscopy Nucleotides Mutation Molecular Medicine Fluorine General Medicine Ligands Biochemistry
Zdroj:	ACS Chemical Biology. 17:2710-2715
ISSN:	1554-8937 1554-8929
Popis:	While there has been recent success in the development of KRasG12C inhibitors, unmet needs for selective inhibitors and tool compounds targeting the remaining oncogenic KRas proteins remain. Here, we applied trifluoromethyl-containing ligands of KRas proteins as competitive probe ligands to assay the occupancy of the switch II pocket by 19F NMR spectroscopy. Structure-activity-relationship studies of probe ligands increased the sensitivity of the assay and identified structures that differentially detected each nucleotide state of KRasG12D. These differences in selectivity, combined with the high resolution of 19F NMR spectroscopy, enabled this method to be expanded to assay both nucleotide states of the protein simultaneously.Abstract Figure
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0694f7ead538454e5fce5d56f179bd4a https://doi.org/10.1021/acschembio.2c00566 Zobrazit plný text záznamu