Crystal structure of PDE4D-Inhibitor complex and study of dimerization sites

Abstract

Cyclic nucleotide phosphodiesterase (PDEs) regulates physiological processes by degrading intracellular second messengers, adenosine-3’,5’-cyclic phosphate or guanosine-3’,5’-cyclic phosphate. The first crystal structure of PDE4D catalytic domain and it’s bound inhibitors, zardaverine and adenine, was determined. Zardaverine and adenine bind to a highly conserved pocket that includes the catalytic binding site pocket. More selective PDE4 inhibitors including rolipram, cilomilast and rofumilast have additional functional group that can utilize the remaining empty space for increased binding energy and selectivity. In the crystal structure, the catalyticd domain of PDE4D possesses an extensive dimerization interface containing residues that are highly conserved in PDE1, 3, 4, 8 and 9. Mutations of R358D or D322R among these interface residues prohibit dimerization of the PDE4D catalytic domain in solution.