Signaling through cAMP and cAMP-dependent protein kinase: Diverse strategies for drug design
Signaling through cAMP and cAMP-dependent protein kinase: Diverse strategies for drug design
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DOI：
10.1016/j.bbapap.2007.10.002
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Kannan, Natarajan
中科院分区：
文献类型：
--
作者：
Taylor, Susan S.;Kim, Choel;Kannan, Natarajan
多年来，cAMP依赖的蛋白激酶催化亚基一直是蛋白激酶超家族的原型，而cAMP结合调节亚基的结构则定义了保守的环核苷酸结合(CNB)基序。然而，只有全酶的结构使我们能够理解调控亚单位抑制和cAMP激活的分子特征。这些结构首次揭示了调节亚单位和CNB结构域的显着延展性。与此同时，它们让我们认识到，催化亚基不仅是催化剂，而且是介导各种蛋白质：蛋白质相互作用的支架。全酶结构也为设计PKA的异构体特异性激活剂和抑制剂提供了一种新的范例。除了与催化亚基结合外，调节亚基还利用其N端二聚化/对接结构域，通过两亲性螺旋基序与A激酶锚定蛋白高亲和力结合。这种靶向机制将PKA定位在其蛋白底物附近，也是PKA信号治疗干预的靶点。(C)2007 Elsevier B.V.保留所有权利。
The catalytic subunit of cAMP-dependent protein kinase has served as a prototype for the protein kinase superfamily for many years while structures of the cAMP-bound regulatory subunits have defined the conserved cyclic nucleotide binding (CNB) motif. It is only structures of the holoenzymes, however, that enable us to appreciate the molecular features of inhibition by the regulatory subunits as well as activation by cAMP. These structures reveal for the first time the remarkable malleability of the regulatory subunits and the CNB domains. At the same time, they allow us to appreciate that the catalytic subunit is not only a catalyst but also a scaffold that mediates a wide variety of protein:protein interactions. The holoenzyme structures also provide a new paradigm for designing isoform-specific activators and inhibitors of PKA. In addition to binding to the catalytic subunits, the regulatory subunits also use their N-terminal dimerization/docking domain to bind with high affinity to A Kinase Anchoring Proteins using an amphipathic helical motif. This targeting mechanism, which localizes PKA near to its protein substrates, is also a target for therapeutic intervention of PKA signaling. (C) 2007 Elsevier B.V. All rights reserved.