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

…, B Lindsay, T Riddell, Z Jiang, RW Allcock…

Index: Day, Jonathan P.; Lindsay, Barbara; Riddell, Tracy; Jiang, Zhong; Allcock, Robert W.; Abraham, Achamma; Sookup, Sebastian; Christian, Frank; Bogum, Jana; Martin, Elisabeth K.; Rae, Robert L.; Anthony, Diana; Rosair, Georgina M.; Houslay, Daniel M.; Huston, Elaine; Baillie, George S.; Klussmann, Enno; Houslay, Miles D.; Adams, David R. Journal of Medicinal Chemistry, 2011 , vol. 54, # 9 p. 3331 - 3347

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Citation Number: 19

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 ...