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Multiple conformations of phosphodiesterase-5 - Implications for enzyme function and drug development
Wang, Huanchen; Liu, Yudong; Huai, Qing; Cai, Jiwen; Zoraghi, Roya; Francis, Sharron H.; Corbin, Jackie D.; Robinson, Howard; Xin, Zhongcheng; Lin, Guiting; Ke, Hengming
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
2006-07-28
DOI10.1074/jbc.M512527200
281期:30页:21469-21479
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology
研究领域[WOS]Biochemistry & Molecular Biology
关键词[WOS]CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES ; CRYSTAL-STRUCTURE ; INHIBITOR SELECTIVITY ; CATALYTIC DOMAIN ; PDE4 ; CGMP ; CAMP ; SILDENAFIL ; BINDING ; SPECIFICITY
英文摘要

Phosphodiesterase-5 (PDE5) is the target for sildenafil, vardenafil, and tadalafil, which are drugs for treatment of erectile dysfunction and pulmonary hypertension. We report here the crystal structures of a fully active catalytic domain of unliganded PDE5A1 and its complexes with sildenafil or icarisid II. These structures together with the PDE5A1-isobutyl-1-methylxanthine complex show that the H-loop ( residues 660-683) at the active site of PDE5A1 has four different conformations and migrates 7-35 angstrom upon inhibitor binding. In addition, the conformation of sildenafil reported herein differs significantly from those in the previous structures of chimerically hybridized or almost inactive PDE5. Mutagenesis and kinetic analyses confirm that the H-loop is particularly important for substrate recognition and that invariant Gly(659), which immediately precedes the H-loop, is critical for optimal substrate affinity and catalytic activity.

语种英语
WOS记录号WOS:000239187300082
Citation statistics
Cited Times:81[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/58310
Collection北京大学第一临床医学院_男科中心
作者单位1.Peking Univ, Hosp 1, Androl Ctr, Beijing 100034, Peoples R China
2.Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA
3.Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
4.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510080, Guangdong, Peoples R China
5.Vanderbilt Univ, Sch Med, Dept Physiol & Mol Biophys, Nashville, TN 37232 USA
6.Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA
7.Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA
Recommended Citation
GB/T 7714
Wang, Huanchen,Liu, Yudong,Huai, Qing,et al. Multiple conformations of phosphodiesterase-5 - Implications for enzyme function and drug development[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2006,281(30):21469-21479.
APA Wang, Huanchen.,Liu, Yudong.,Huai, Qing.,Cai, Jiwen.,Zoraghi, Roya.,...&Ke, Hengming.(2006).Multiple conformations of phosphodiesterase-5 - Implications for enzyme function and drug development.JOURNAL OF BIOLOGICAL CHEMISTRY,281(30),21469-21479.
MLA Wang, Huanchen,et al."Multiple conformations of phosphodiesterase-5 - Implications for enzyme function and drug development".JOURNAL OF BIOLOGICAL CHEMISTRY 281.30(2006):21469-21479.
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