Tapping the translation potential of cAMP signalling: molecular basis for selectivity in cAMP agonism and antagonism as revealed by NMR
Tapping the translation potential of cAMP signalling: molecular basis for selectivity in cAMP agonism and antagonism as revealed by NMR
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DOI：
10.1042/bst20130282
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发表时间：
2014-04-01
影响因子：
3.9
通讯作者：
Melacini, Giuseppe
中科院分区：
文献类型：
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作者：
Boulton, Stephen;Akimoto, Madoka;Melacini, Giuseppe
真核生物cBD(cAMP结合域)控制多种细胞功能(如磷酸化、鸟嘌呤交换和离子通道门控)。因此，cAMP依赖的信号通路的操纵具有很高的翻译潜力。然而，真核生物CBD的无处不在也在选择性方面构成了挑战。在充分挖掘cAMP信号的翻译潜力之前，了解选择性cAMP激动剂和拮抗剂的结构基础是至关重要的。最近的核磁共振研究表明，结构上同源的CBD对几种CBD配体的反应不同，这些意想不到的差异出现在结合(即亲和力)或变构(即自抑制平衡的调节)水平上。在本文中，我们具体讨论了高度保守的CBD折叠是如何与cAMP结合的，与其他真核cAMP受体，如EPAC(由cAMP直接激活的交换蛋白)和HCN(超极化激活的环核苷酸解调通道)相比，PKA(蛋白激酶A)具有明显不同的亲和力。CAMP亲和力的一个主要决定因素被假设为apo-CBD的自我抑制平衡的位置，这似乎在不同的CBD之间存在显著差异。这些分析可能有助于开发选择性CBD效应器，作为治疗心血管疾病的潜在药物先导。
Eukaryotic CBDs (cAMP-binding domains) control multiple cellular functions (e.g. phosphorylation, guanine exchange and ion channel gating). Hence the manipulation of cAMP-dependent signalling pathways has a high translational potential. However, the ubiquity of eukaryotic CBDs also poses a challenge in terms of selectivity. Before the full translational potential of CAMP signalling can be tapped, it is critical to understand the structural basis for selective cAMP agonism and antagonism. Recent NMR investigations have shown that structurally homologous CBDs respond differently to several CBD ligands and that these unexpected differences arise at the level of either binding (i.e. affinity) or allostery (i.e. modulation of the autoinhibitory equilibria). In the present article, we specifically address how the highly conserved CBD fold binds cAMP with markedly different affinities in PKA (protein kinase A) relative to other eukaryotic cAMP receptors, such as Epac (exchange protein directly activated by cAMP) and HCN (hyperpolarization-activated cyclic-nucleotidemodulated channel). A major emerging determinant of cAMP affinity is hypothesized to be the position of the autoinhibitory equilibrium of the apo-CBD, which appears to vary significantly across different CBDs. These analyses may assist the development of selective CBD effectors that serve as potential drug leads for the treatment of cardiovascular diseases.