...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct
【24h】

Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct

机译：由近全长构建体的X射线结构推导的磷酸二酯酶2A的变构调节机理

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

We report the X-ray crystal structure of a phosphodiesterase (PDE) that includes both catalytic and regulatory domains. PDE2A (215-900) crystallized as a dimer in which each subunit had an extended organization of regulatory GAF-A and GAF-B and catalytic domains connected by long α-helices. The subunits cross at the GAF-B/ catalytic domain linker, and each side of the dimer contains in series the GAF-A and GAF-B of one subunit and the catalytic domain of the other subunit. A dimer interface extends over the entire length of the molecule. The substrate binding pocket of each catalytic domain is occluded by the H-loop. We deduced from comparisons with structures of isolated, ligand-bound catalytic subunits that the H-loop swings out to allow substrate access. However, in dimeric PDE2A (215-900), the H-loops of the two catalytic subunits pack against each other at the dimer interface, necessitating movement of the catalytic subunits to allow for H-loop movement. Comparison of the unliganded GAF-B of PDE2A (215-900) with previous structures of isolated, cGMP-bound GAF domains indicates that cGMP binding induces a significant shift in the GAF-B/catalytic domain linker. We propose that cGMP binding to GAF-B causes movement, through this linker region, of the catalytic domains, such that the H-loops no longer pack at the dimer interface and are, instead, free to swing out to allow substrate access. This increase in substrate access is proposed as the basis for PDE2A activation by cGMP and may be a general mechanism for regulation of all PDEs.
机译：我们报告了包括催化域和调节域的磷酸二酯酶（PDE）的X射线晶体结构。 PDE2A（215-900）结晶为二聚体，其中每个亚基都有调节性GAF-A和GAF-B的扩展组织，以及通过长α螺旋连接的催化结构域。亚基在GAF-B /催化结构域接头处交叉，并且二聚体的每一侧串联包含一个亚基的GAF-A和GAF-B以及另一亚基的催化域。二聚体界面在分子的整个长度上延伸。每个催化结构域的底物结合口袋被H-环封闭。我们通过与分离的，配体结合的催化亚基的结构比较得出结论，H环向外摆动以允许底物进入。但是，在二聚体PDE2A（215-900）中，两个催化亚基的H环在二聚体界面处相互堆积，必须移动催化亚基以允许H环移动。 PDE2A的未配体GAF-B（215-900）与以前的分离的，与cGMP结合的GAF域的结构比较，表明cGMP结合诱导了GAF-B /催化域接头的显着变化。我们提出，cGMP与GAF-B的结合会导致通过该连接区的催化结构域运动，从而使H环不再堆积在二聚体界面上，而是可以自由摆动以允许底物进入。底物可及性的增加被认为是cGMP激活PDE2A的基础，并且可能是调节所有PDE的通用机制。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号