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

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Item Type:	Article
Title:	Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4)
Creators Name:	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. and Adams, D.R.
Abstract:	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 enzyme's 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 enzyme's 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 enzyme's protein association partnerships.
Keywords:	CHO Cells, Catalytic Domain, Cyclic Nucleotide Phosphodiesterases Type 4, Isoenzymes, Molecular Models, Phosphodiesterase 4 Inhibitors, Pyridines, Rolipram, Signal Transducing Adaptor Proteins, Spiro Compounds, Stereoisomerism, Structure-Activity Relationship, Xanthines, X-Ray Crystallography, Animals, Cricetinae, Cricetulus
Source:	Journal of Medicinal Chemistry
ISSN:	0022-2623
Publisher:	American Chemical Society
Volume:	54
Number:	9
Page Range:	3331-3347
Date:	12 May 2011
Official Publication:	https://doi.org/10.1021/jm200070e
PubMed:	View item in PubMed

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