Systematic investigation of protein–small molecule interactions

Abstract

Cell signaling is extensively wired between cellular components to sustain cell proliferation, differentiation, and adaptation. The interaction network is often manifested in how protein function is regulated through interacting with other cellular components including small molecule metabolites. While many biochemical interactions have been established as reactions between protein enzymes and their substrates and products, much less is known at the system level about how small metabolites regulate protein functions through allosteric binding. In the past decade, study of protein-small molecule interactions has been lagging behind other types of interactions. Recent technological advances have explored several high-throughput platforms to reveal many ''unexpected'' protein-small molecule interactions that could have profound impact on our understanding of cell signaling. These interactions will help bridge gaps in existing regulatory loops of cell signaling and serve as new targets for medical intervention. In this review, we summarize recent advances of systematic investigation of protein-metabolite/small molecule interactions, and discuss the impact of such studies and their potential impact on both biological researches and medicine.

Targeting Lipid Esterases in Mycobacteria Grown Under Different Physiological Conditions Using Activity-based Profiling with Tetrahydrolipstatin (THL)

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Genome-Scale Architecture of Small Molecule Regulatory Networks and the Fundamental Trade-Off between Regulation and Enzymatic Activity

“…So far, high-throughput experimental assays for discovering small molecule regulatory interactions have been technically limited (Feng et al, 2014; Li et al, 2013; Nikolaev et al, 2016; Orsak et al, 2012; Reinhard et al, 2015; Savitski et al, 2014), while hybrid approaches that integrate experimental data with computational models are not scalable and typically focus on central carbon metabolism (Hackett et al, 2016; Link et al, 2014, 2013; Schueler-Furman and Wodak, 2016). …”

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“…Target identification and validation remain to be a bottleneck in drug discovery (Lomenick et al 2011). A handful of new technologies to study the interactions between small molecules and target proteins have been invented in the past two decades by means of chemical biology (Li et al 2013b). This emerging discipline applies modern chemistry theories, research methods and experimental tools to investigation of basic questions in biology, aiming at revealing the nature of life.…”