Abstract
In-cell nuclear magnetic resonance (NMR) is a method to provide the structural information of a target at an atomic level under physiological conditions and a full view of the conformational changes of a protein caused by ligand binding, post-translational modifications or protein–protein interactions in living cells. Previous in-cell NMR studies have focused on proteins that were overexpressed in bacterial cells and isotopically labeled proteins injected into oocytes of Xenopus laevis or delivered into human cells. Applications of in-cell NMR in probing protein modifications, conformational changes and ligand bindings have been carried out in mammalian cells by monitoring isotopically labeled proteins overexpressed in living cells. The available protocols and successful examples encourage wide applications of this technique in different fields such as drug discovery. Despite the challenges in this method, progress has been made in recent years. In this review, applications of in-cell NMR are summarized. The successful applications of this method in mammalian and bacterial cells make it feasible to play important roles in drug discovery, especially in the step of target engagement.
Highlights
Solution nuclear magnetic resonance (NMR) [1], X-ray crystallography and cryogenic electron microscopy [2] are important tools for obtaining the structures of biomolecules at atomic resolution [3]
Solution NMR spectroscopy is able to investigate protein structures and dynamics under solution conditions because the targets can be studied in different buffers and at various temperatures [10]
Solution NMR spectroscopy has been used in various research topics, including protein–protein, protein–nucleotide complexes, and membrane proteins, to provide useful information in order to understand protein structure and function [17,18,19,20]
Summary
Solution nuclear magnetic resonance (NMR) [1], X-ray crystallography and cryogenic electron microscopy (cryo-EM) [2] are important tools for obtaining the structures of biomolecules at atomic resolution [3]. Solution NMR spectroscopy has been used in various research topics, including protein–protein, protein–nucleotide complexes, and membrane proteins, to provide useful information in order to understand protein structure and function [17,18,19,20]. NMR spectroscopy is a powerful method that can be used in combination with other methods, such as X-ray, cryo-EM, bioinformatics and SAXS/SANS, providing different views on the structures and dynamics of biomolecules, and their functional complexes in solution [27,28,29,30,31]. This review only summarizes recent progress in in-cell NMR using solution NMR spectroscopy and discusses the challenges and potential applications in drug discovery
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