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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • CHO Cells
  • Catalytic Domain
  • Cricetinae
  • Cricetulus
  • Crystallography, X-Ray
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Models, Molecular
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Rolipram / chemistry
  • Rolipram / pharmacology
  • Sequestosome-1 Protein
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xanthines / chemistry
  • Xanthines / pharmacology

Substances

  • Adaptor Proteins, Signal Transducing
  • Isoenzymes
  • Phosphodiesterase 4 Inhibitors
  • Pyridines
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Spiro Compounds
  • Xanthines
  • cipamfylline
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram
  • ibudilast