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A Toolbox of Structural Biology and Enzyme Kinetics Reveals the Case for ERK Docking Site Inhibition

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Next Generation Kinase Inhibitors

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Abstract

Extracellular signal–regulated kinase (ERK) is a mitogen-activated protein kinase (MAPK) that mediates cellular processes such as proliferation, differentiation, cell motility, and survival. Dysregulation of the ERK signaling pathway is believed to have a protumorigenic role in many cancers, and studies also implicate it in a variety of other proliferative diseases. Within the ERK signaling pathway, protein-protein interactions via enzyme-docking sites help generate signal specificity and direct ERK to subsequent binding partners or substrates. ERK possesses two known docking sites that are distinct from its catalytic site: the D- and F- recruitment sites (DRS and FRS). Over time, our group has characterized these sites through a combination of structural and kinetic studies, including computational and biochemical techniques, centering around a model ERK substrate EtsΔ138 (residues 1–138 of the transcription factor Ets-1). These studies are part of a growing effort to elucidate new insights into ERK signaling and to evaluate the role of each binding site in specific ERK interactions. Furthermore, the development of inhibitors that target these docking sites offers a way to impede both catalytic and noncatalytic functions of ERK, which may provide therapeutic benefit in disease states driven by ERK signaling. Here, we describe the features of the DRS and FRS of ERK, their roles in the phosphorylation of EtsΔ138, and the status, mechanisms, and implications of targeting these sites with inhibitors.

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Notes

  1. 1.

    Underlined amino acid codes denote basic (ψ) and hydrophobic (φA and φB) residues of the D-site sequence.

  2. 2.

    Underlined residues correspond to the F-site sequence FXFP

  3. 3.

    IC50 values are concentrations of an antagonist molecule that are required to observe a half-maximal inhibitory effect. These measurements are dependent on enzyme concentration, presence of competitive substrates, and duration of exposure to enzyme (if the inhibitors are time-dependent enzyme inactivators).

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Authors and Affiliations

  1. Targeted Therapeutic Drug Discovery and Development Program, The University of Texas at Austin, Austin, TX, USA

    Rachel M. Sammons & Kevin N. Dalby

  2. Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA

    Kevin N. Dalby

  3. Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA

    Kevin N. Dalby

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  1. Rachel M. Sammons
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  2. Kevin N. Dalby
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Correspondence to Kevin N. Dalby .

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  1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA

    Paul Shapiro

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Sammons, R.M., Dalby, K.N. (2020). A Toolbox of Structural Biology and Enzyme Kinetics Reveals the Case for ERK Docking Site Inhibition. In: Shapiro, P. (eds) Next Generation Kinase Inhibitors. Springer, Cham. https://doi.org/10.1007/978-3-030-48283-1_6

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