Exploring protein conformations with limited proteolysis coupled to mass spectrometry

Limited proteolysis coupled to mass spectrometry (LiP-MS) has emerged as a powerful proteomic tool for studying protein conformations. Since its introduction in 2014, LiP-MS has expanded its scope to explore complex biological systems and shed light on disease mechanisms, and has been used for protein drug research. This review discusses the evolution of the technique, recent technical advances, including enhanced protocols and integration of machine learning, and diverse applications across various experimental models. Despite its achievements, challenges in protein extraction and conformotypic peptide identification remain. Ongoing methodological refinements will be crucial to overcome these challenges and enhance the capabilities of the technique. However, LiP-MS offers significant potential for future discoveries in structural proteomics and medical research.