Elucidation of a Structural Basis for the Inhibitor-Driven, p62 (SQSTM1)-Dependent Intracellular Redistribution of cAMP Phosphodiesterase-4A4 (PDE4A4) was written by 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.. And the article was included in Journal of Medicinal Chemistry in 2011.Category: naphthyridine This article mentions the following:
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. In the experiment, the researchers used many compounds, for example, 6-Amino-8-bromo-1,7-naphthyridine (cas: 5912-35-6Category: naphthyridine).
6-Amino-8-bromo-1,7-naphthyridine (cas: 5912-35-6) belongs to naphthyridine derivatives. The naphthyridines have 10 delocalized π-electrons located in five molecular orbitals, each of which is distorted by the presence of the nitrogen atoms causing an electron drift in that direction. Halogen atoms attached to the naphthyridine moiety can be easily replaced by other nucleophiles such as alkoxides and amines.Category: naphthyridine
Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem