Most therapeutics are designed to alter the activities of proteins. From metabolic enzymes to cell surface receptors, connecting the function of a protein to a cellular phenotype, to the activity of a drug and to a clinical outcome represents key mechanistic milestones during drug development. Yet, even for therapeutics with exquisite specificity, the sequence of events following target engagement can be complex. Interconnected communities of structural, metabolic and signalling proteins modulate diverse downstream effects that manifest as interindividual differences in efficacy, adverse effects and resistance to therapy. Recent advances in mass spectrometry proteomics have made it possible to decipher these complex relationships and to understand how factors such as genotype, cell type, local environment and external perturbations influence them. In this Review, we explore how proteomic technologies are expanding our understanding of protein communities and their responses to large- and small-molecule therapeutics.

大多数疗法旨在改变蛋白质的活性。从代谢酶到细胞表面受体，再将蛋白质的功能与细胞表型，药物的活性和临床结果联系起来，代表了药物开发过程中的关键机械里程碑。但是，即使对于具有出色特异性的治疗剂，靶标参与后的事件顺序也可能很复杂。结构，代谢和信号蛋白的相互联系的社区调节各种下游作用，表现为功效，不良反应和对治疗的抵抗力之间的个体差异。质谱蛋白质组学的最新进展使人们有可能破译这些复杂的关系，并了解诸如基因型，细胞类型，局部环境和外部干扰等因素如何影响它们。