Membrane Protein Structure in Live Cells: Methodology for Studying Drug Interaction by Mass Spectrometry-Based Footprinting
Mass spectrometry-based footprinting is an emerging approach for studying protein structure. Because integral membrane proteins are difficult targets for conventional structural biology, we recently developed a mass spectrometry (MS) footprinting method to probe membrane protein–drug interactions in live cells. This method can detect structural differences between apo and drug-bound states of membrane proteins, with the changes inferred from MS quantification of the cysteine modification pattern, generated by residue-specific chemical labeling. Here, we describe the experimental design, interpretation, advantages, and limitations of using cysteine footprinting by taking as an example the interaction of warfarin with vitamin K epoxide reductase, a human membrane protein. Compared with other structural methods, footprinting of proteins in live cells produces structural information for the near native state. Knowledge of cellular conformational states is a necessary complement to the high-resolution structur...
Authors:
Guomin Shen; Shuang Li; Weidong Cui; Shixuan Liu; Yihu Yang; Michael Gross; Weikai Li
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