Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4)

Jonathan P. Day, Barbara Lindsay, Tracy Riddell, Zhong Jiang, Robert W. Allcock, Achamma Abraham, Sebastian Sookup, Frank Christian, Jana Bogum, Elisabeth K. Martin, Robert L. Rae, Diana Anthony, Georgina M. Rosair, Daniel M. Houslay, Elaine Huston, George S. Baillie, Enno Klussmann, Miles D. Houslay, David R. Adams

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30 Citations (Scopus)

Abstract

Figure Presented. A survey of PDE4 inhibitors reveals that some compounds trigger intracellular aggregation of PDE4A4 into accretion foci through association with the ubiquitin-binding scaffold protein p62 (SQSTM1). We show that this effect is driven by inhibitor occupancy of the catalytic pocket and stabilization of a capped state in which a sequence within the enzymes upstream conserved region 2 (UCR2) module folds across the catalytic pocket. Only certain inhibitors cause PDE4A4 foci formation, and the structural features responsible for driving the process are defined. Switching to the UCR2-capped state induces conformational transition in the enzymes regulatory N-terminal portion, facilitating protein association events responsible for reversible aggregate assembly. PDE4-selective inhibitors able to trigger relocalization of PDE4A4 into foci can therefore be expected to exert actions on cells that extend beyond simple inhibition of PDE4 catalytic activity and that may arise from reconfiguring the enzymes protein association partnerships. © 2011 American Chemical Society.

Original languageEnglish
Pages (from-to)3331-3347
Number of pages17
JournalJournal of Medicinal Chemistry
Volume54
Issue number9
DOIs
Publication statusPublished - 12 May 2011

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    Day, J. P., Lindsay, B., Riddell, T., Jiang, Z., Allcock, R. W., Abraham, A., Sookup, S., Christian, F., Bogum, J., Martin, E. K., Rae, R. L., Anthony, D., Rosair, G. M., Houslay, D. M., Huston, E., Baillie, G. S., Klussmann, E., Houslay, M. D., & Adams, D. R. (2011). Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4). Journal of Medicinal Chemistry, 54(9), 3331-3347. https://doi.org/10.1021/jm200070e