Protein biomarkers in precision medicine: Integrating structure, dynamics, and structural proteomics for personalized therapy

Precision medicine aims to individualize diagnostics and treatment of individual patients based on the molecular processes of the heterogeneity of diseases. Although genomics has made it possible to identify patient-specific variants (in large numbers), a clinical translation of these variants increasingly relies on the way in which they modify protein structure, dynamics, and function. Protein biomarkers are not just signs of abundance and they can typically play a disease-specific conformational state, post-translational modifications, and interaction networks that have a direct bearing on diagnosis, prognosis, and therapeutic response. This review tells about the new role of protein structural biology and structural proteomics to develop precision medicine. We discuss how patient-derived genetic variants mapped on to three-dimensional protein structures make it possible to stratify diseases mechanistically, enhance the ability to understand variant pathogenicity and inform personal therapeutic choices. We point out structure-directed methods of biomarker discovery, such as hydrogen deuterium exchange mass spectrometry, crosslinking mass spectrometry and conformation-specific assays, which can detect disease-relevant states of protein that cannot be reached by traditional techniques. Moreover, we address how the protein structure and dynamics can guide the choice of pharmacogenomics and targeted therapy using some representative clinical cases, such as cancer driven by a kinase, amyloid disorders, which are a subset of protein misfolding disorders . Combination of structural proteomics and multi-omics data would offer a systems-based but mechanistically based paradigm of genotype-to-phenotype relationship. We find that to transform the findings of biomarkers into clinical actionable precision diagnostics and targeted therapeutic plans, the incorporation of protein structural information is needed.