Crystal structure of phosphodiesterase 4D and inhibitor complex

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Cyclic nucleotide phosphodiesterases (PDEs) regulate 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 a bound inhibitor, zardaverine, was determined. Zardaverine binds to a highly conserved pocket that includes the catalytic metal binding site. Zardaverine fills only a portion of the active site pocket. More selective PDE4 inhibitors including rolipram, cilomilast and roflumilast have additional functional groups that can utilize the remaining empty space for increased binding energy and selectivity. In the crystal structure, the catalytic 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. (C) 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.
Publisher
ELSEVIER SCIENCE BV
Issue Date
2002-10
Language
English
Article Type
Article
Keywords

PDE4 INHIBITORS; DOMAIN; IDENTIFICATION; SPECIFICITY; MUTATION; ANALOGS; PROTEIN; POTENT; FAMILY

Citation

FEBS LETTERS, v.530, no.1-3, pp.53 - 58

ISSN
0014-5793
URI
http://hdl.handle.net/10203/11494
Appears in Collection
CH-Journal Papers(저널논문)
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