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

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Day JP, Lindsay B, Riddell T, Jiang Z, Allcock RW, Abraham A, Sookup S, Christian F, Bogum J, Martin EK, Rae RL, Anthony D, Rosair GM, Houslay DM, Huston E, Baillie GS, Klussmann E, Houslay MD, Adams DR

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

J Med Chem. 2011 May 12;54(9):3331-47. doi: 10.1021/jm200070e. Epub 2011 Apr 13.

PubMed ID

21456625 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-[8-(3-nitrophenyl)-1,7-naphthyridin-6-yl]benzoic acid	cAMP-specific 3',5'-cyclic phosphodiesterase 4A	IC 50 (nM)	29	N/A	N/A	Details
4-[8-(3-nitrophenyl)-1,7-naphthyridin-6-yl]benzoic acid	cAMP-specific 3',5'-cyclic phosphodiesterase 4A	EC 50 (nM)	20	N/A	N/A	Details
Ibudilast	cAMP-specific 3',5'-cyclic phosphodiesterase 4A	IC 50 (nM)	1300	N/A	N/A	Details
Ibudilast	cAMP-specific 3',5'-cyclic phosphodiesterase 4A	EC 50 (nM)	900	N/A	N/A	Details