Crystal structure of phosphodiesterase 4D and inhibitor complex1

FEBS Letters

Markowitz, Joseph¹  Lee, Hayyoung²  Lee, Jie-Oh³  Lee, Mi Eun³ 

[1] Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;Institute of Biotechnology, Chungnam National University, Kung-dong, Yusong-gu, Daejon 305-764, South Korea;Department of Chemistry, Korea Advanced Institute of Science and Technology, 373-1 Kusong-dong, Yusong-gu, Daejon 305-701, South Korea

关键词: Phosphodiesterase-4;    Zardaverine;    Rolipram;    Cyclic adenosine-3′;    5′-phosphate;    X-ray crystal structure;    PDE;    phosphodiesterase;    cAMP;    adenosine-3′;    5′-cyclic phosphate;    cGMP;    guanosine-3′;    5′-cyclic phosphate;    NCS;    non-crystallographic symmetry;   

DOI  :  10.1016/S0014-5793(02)03396-3

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown