Highly functionalized terpyridines as competitive inhibitors of AKAP-PKA interactions.
Highly functionalized terpyridines as competitive inhibitors of AKAP-PKA interactions.
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DOI：
10.1002/anie.201304686
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发表时间：
2013-11-11
影响因子：
16.6
通讯作者：
Klussmann, Enno
中科院分区：
文献类型：
--
作者：
Schaefer, Gesa;Milic, Jelena;Eldahshan, Adeeb;Goetz, Frank;Zuehlke, Kerstin;Schillinger, Christian;Kreuchwig, Annika;Elkins, Jonathan M.;Abdul Azeez, Kamal R.;Oder, Andreas;Moutty, Marie C.;Masada, Nanako;Beerbaum, Monika;Schlegel, Brigitte;Niquet, Sylvia;Schmieder, Peter;Krause, Gerd;von Kries, Jens Peter;Cooper, Dermot M. F.;Knapp, Stefan;Rademann, Joerg;Rosenthal, Walter;Klussmann, Enno
蛋白激酶A （PKA）是一种普遍存在的激酶，可磷酸化多种底物。a激酶锚定蛋白（AKAPs）通过将激酶拴在不同的细胞室中，从而限制PKA进入特定的底物池，从而赋予PKA信号的特异性akap和PKA之间的相互作用在大量生理相关过程中发挥关键作用，如精氨酸-加压素（AVP）介导的肾主细胞水重吸收；AVP触发PKA磷酸化水通道水通道蛋白-2 （AQP2）。然后AQP2从细胞内囊泡重新分布到质膜，从而促进原尿中的水分重吸收。只有当PKA与akap相互作用时，再分布才会发生依赖于AKAP-PKA相互作用的细胞过程失调导致或与疾病相关。[1b， 3]例如，在心力衰竭中，AVP水平升高通过上述机制导致过度的水潴留。心力衰竭时心肌细胞收缩力降低；收缩性的控制主要取决于AKAP-PKA的相互作用PKA全酶是一种四聚体，由一个调节（RIα、RIβ、RIIα或RIIβ）二聚体和两个催化(C)亚基组成，每个亚基与一个rproprotomer结合。当cAMP与R亚基结合时，C亚基解离并磷酸化它们的底物。PKA与AKAPs的相互作用是由R亚基二聚体的二聚化/对接（D/D）结构域和AKAPs的RII结合结构域（RBD）介导的。二聚的D/D结构域形成疏水口袋，直接与14-25个氨基酸的长α-螺旋RBD相互作用从不同akap的rbd衍生的合成肽以纳米摩尔的亲和力结合R亚基，例如，AKAP18δ衍生的AKAP18δ- l314e （KD= 4 nm；见图S1和S2以及支持信息中的表S2）这些肽有效地抑制了AKAP-PKA的相互作用例如，AKAP18δ-L314E[7]和Ht31的膜透性版本[2a]（来自AKAP-Lbc）在培养的主细胞中消除了avp诱导的AQP2的再分布。因此，AKAP-PKA相互作用的破坏甚至似乎有利于治疗与avp依赖性过度水潴留相关的疾病，如心力衰竭由于多肽的细胞膜渗透性和稳定性普遍较低，因此它们在细胞和动物研究以及药物开发中的应用受到限制。小分子和非肽螺旋模拟物被认为是肽的替代品，因此开发了抑制AKAP-PKA相互作用的小分子FMP-API-1。然而，FMP-API-1也能激活PKA，
Protein kinase A (PKA) is a ubiquitous kinase that phosphorylates a broad variety of substrates. A-kinase anchoring proteins (AKAPs) confer specificity to PKA signaling by tethering the kinase to distinct cellular compartments, thereby limiting the access of PKA to a defined pool of its substrates.[1] Interactions between AKAPs and PKA play key roles in a plethora of physiologically relevant processes such as arginine-vasopressin (AVP) mediated water reabsorption in renal principal cells; AVP triggers PKA phosphorylation of the water channel aquaporin-2 (AQP2). AQP2 then redistributes from intracellular vesicles into the plasma membrane, thereby facilitating water reabsorption from primary urine. The redistribution only occurs if PKA interacts with AKAPs.[2] Dysregulation of cellular processes that depend on AKAP–PKA interactions causes or is associated with diseases.[1b, 3] For example, in heart failure, elevated AVP levels contribute to the excessive water retention by the above-described mechanism. Cardiac myocyte contractility is decreased in the failing heart; the control of contractility crucially depends on AKAP–PKA interactions.[4] PKA holoenzyme is a tetramer consisting of a dimer of regulatory (RIα, RIβ, RIIα, or RIIβ) and two catalytic (C) subunits each bound to an Rprotomer. Upon binding of cAMP to the R subunits, the C subunits dissociate and phosphorylate their substrates. Interactions of PKA with AKAPs are mediated by the dimerization/docking (D/D) domains of R subunit dimers and the RII binding domain (RBD) of AKAPs. Dimerized D/D domains form a hydrophobic pocket that directly interacts with the 14–25 amino acid long α-helical RBD.[5] Synthetic peptides derived from RBDs of different AKAPs bind R subunits with nanomolar affinity, for example, AKAP18δ-L314E from AKAP18δ (KD= 4 nm; see Figures S1 and S2 as well as Table S2 in the Supporting Information).[6] Such peptides effectively inhibit AKAP–PKA interactions.[1] For example, membrane-permeable versions of AKAP18δ-L314E [7] and Ht31 [2a](from AKAP-Lbc) abolish the AVP-induced redistribution of AQP2 in cultured principal cells. Thus disruption of AKAP–PKA interactions even appears beneficial for the treatment of diseases, such as heart failure, that are associated with AVP-dependent excessive water retention.[3] As a consequence of their generally low membrane permeability and stability, peptides have limitations with regard to their use in cell and animal studies and for drug development. Small molecules and nonpeptide helix mimetics are considered as alternatives to peptides, and thus the small molecule FMP-API-1 was developed that inhibits AKAP–PKA interactions. However, FMP-API-1 also activates PKA,
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DOI：
10.1038/nrm3432
发表时间：
2012-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.2
作者：
Thompson, Sam;Hamilton, Andrew D.
通讯作者：
Hamilton, Andrew D.
DOI：
10.1016/j.str.2009.12.012
发表时间：
2010-02-10
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Sarma GN;Kinderman FS;Kim C;von Daake S;Chen L;Wang BC;Taylor SS
通讯作者：
Taylor SS
影响因子：
2
作者：
Cailly, T;Fabis, F;Rault, S
通讯作者：
Rault, S
影响因子：
2.8
作者：
Kaminski, T;Gros, P;Fort, Y
通讯作者：
Fort, Y