Cyclic nucleotide phosphodiesterases (PDEs) control cellular concentration of """"""""second messengers"""""""" cAMP and cGMP that modulate many metabolic processes. Human genome encodes 21 PDE genes that are categorized into 11 families and express over 100 isoforms of proteins via RNA splicing. Selective inhibitors of PDEs have been studied as therapeutic agents for various human diseases. An example is PDE5-selective inhibitor sildenafil (Viagra) that is a drug for treatment of erectile dysfunction and pulmonary hypertension. The studies of our last grant proposal have led to publications of 14 original research papers, and provided insight into the mechanisms of substrate specificity and inhibitor selectivity of PDEs. However, no structures of full-length or fragments with both regulatory and catalytic domains are available so that it remains unknown how the PDE catalysis is regulated by their regulatory domains. It is also a puzzle how PDEs cross-talk to proteins in other signaling pathways. This proposal aims at understanding regulation of PDE activities by their regulatory domains, PDE interaction with other proteins, and PDE inhibitor discovery.
The specific aims i nclude: (1) structural and biochemical studies of the near-full length PDE5A1 and its complexes with substrate and inhibitors, (2) structures of PDE8A and its complexes with inhibitors and with the binding protein I?B?, (3) structural and kinetic studies on PDE1A in complex with calmodulin, and (4) structure-based discovery of PDE4 inhibitors for treatment of inflammatory diseases.
Specific aims I, II, and III will not only reveal the structural information of near full-length PDE5, PDE8 and PDE1, but also provide insight into the catalytic mechanisms of these PDE families. The complex structures of PDE1-calmodulin and PDE8-I?B? will shed light on the potential roles of the PDE families in the signaling pathways.
Specific aim I V may lead to discovery of a new category of PDE4 inhibitors for treatment of human diseases.
Phosphodiesterases (PDEs) are sole enzymes degrading cellular second messengers cAMP and cGMP that play important roles in physiological processes. This proposal aims at (1) structural and biochemical studies of near-full length PDE1, 5, and 8 and their interactions with calmodulin and IkB and (2) structure-based discovery of PDE4 selective inhibitors. These studies will not only provide insight into the regulation of PDE catalysis and interactions with proteins in other signaling pathways, but also lead to discovery of PDE4 inhibitors for treatment of human diseases.
|Huang, Manna; Shao, Yongxian; Hou, Jianying et al. (2015) Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor. Mol Pharmacol 88:836-45|
|Shao, Yong-xian; Huang, Manna; Cui, Wenjun et al. (2014) Discovery of a phosphodiesterase 9A inhibitor as a potential hypoglycemic agent. J Med Chem 57:10304-13|
|Shang, Na-Na; Shao, Yong-Xian; Cai, Ying-Hong et al. (2014) Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure. Biochem Pharmacol 89:86-98|
|Tian, Yuanyuan; Cui, Wenjun; Huang, Manna et al. (2014) Dual specificity and novel structural folding of yeast phosphodiesterase-1 for hydrolysis of second messengers cyclic adenosine and guanosine 3',5'-monophosphate. Biochemistry 53:4938-45|
|Jansen, Chimed; Wang, Huanchen; Kooistra, Albert J et al. (2013) Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure. J Med Chem 56:2087-96|
|Park, Sung-Jun; Ahmad, Faiyaz; Philp, Andrew et al. (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148:421-33|
|Wang, Huanchen; Kunz, Stefan; Chen, Gong et al. (2012) Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and Implications for design of parasite selective inhibitors. J Biol Chem 287:11788-97|
|Yuan, Qinghui; He, Lin; Ke, Hengming (2012) A potential substrate binding conformation of ýý-lactams and insight into the broad spectrum of NDM-1 activity. Antimicrob Agents Chemother 56:5157-63|
|Meng, Fei; Hou, Jing; Shao, Yong-Xian et al. (2012) Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design. J Med Chem 55:8549-58|
|Liu, Junli; Xia, Hongguang; Kim, Minsu et al. (2011) Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13. Cell 147:223-34|
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