Flaxman Hope A, Woo Christina M
Department of Chemistry and Chemical Biology, Harvard University , 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
Biochemistry. 2018 Jan 16;57(2):186-193. doi: 10.1021/acs.biochem.7b01038. Epub 2017 Nov 10.
Mapping small molecule interactions throughout the proteome provides the critical structural basis for functional analysis of their impact on biochemistry. However, translation of mass spectrometry-based proteomics methods to directly profile the interaction between a small molecule and the whole proteome is challenging because of the substoichiometric nature of many interactions, the diversity of covalent and noncovalent interactions involved, and the subsequent computational complexity associated with their spectral assignment. Recent advances in chemical proteomics have begun fill this gap to provide a structural basis for the breadth of small molecule-protein interactions in the whole proteome. Innovations enabling direct characterization of the small molecule interactome include faster, more sensitive instrumentation coupled to chemical conjugation, enrichment, and labeling methods that facilitate detection and assignment. These methods have started to measure molecular interaction hotspots due to inherent differences in local amino acid reactivity and binding affinity throughout the proteome. Measurement of the small molecule interactome is producing structural insights and methods for probing and engineering protein biochemistry. Direct structural characterization of the small molecule interactome is a rapidly emerging area pushing new frontiers in biochemistry at the interface of small molecules and the proteome.
绘制小分子与整个蛋白质组之间的相互作用图谱，为分析其对生物化学影响的功能提供了关键的结构基础。然而，将基于质谱的蛋白质组学方法转化为直接描绘小分子与整个蛋白质组之间的相互作用具有挑战性，这是因为许多相互作用具有亚化学计量性质、涉及的共价和非共价相互作用具有多样性，以及随后与其光谱归属相关的计算复杂性。化学蛋白质组学的最新进展已开始填补这一空白，为整个蛋白质组中小分子与蛋白质相互作用的广度提供结构基础。能够直接表征小分子相互作用组的创新技术包括更快、更灵敏的仪器，以及与化学偶联、富集和标记方法相结合，这些方法有助于检测和归属。由于整个蛋白质组中局部氨基酸反应性和结合亲和力的固有差异，这些方法已开始用于测量分子相互作用热点。小分子相互作用组的测量正在产生结构见解以及探测和改造蛋白质生物化学的方法。小分子相互作用组的直接结构表征是一个迅速兴起的领域，正在小分子与蛋白质组的界面推动生物化学的新前沿。
