Mechanism of Action of an EPAC1-Selective Competitive Partial Agonist.
Mechanism of Action of an EPAC1-Selective Competitive Partial Agonist.
复制标题
EPAC1 选择性竞争性部分激动剂的作用机制。
DOI：
--
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
G. Melacini
中科院分区：
文献类型：
--
作者：
Hongzhao Shao;H. Mohamed;Stephen Boulton;Jinfeng Huang;Pingyuan Wang;Haiying Chen;Jia Zhou;Urszula Luchowska;Nicholas G. Jentsch;A. Armstrong;Jakob Magolan;S. Yarwood;G. Melacini
由cAMP激活的交换蛋白（EPAC）是一种很有前途的药物靶标，适用于从神经变性和感染到癌症和心血管疾病的广泛疾病。最近发现了一种新的EPAC亚型1（EPAC 1）的部分激动剂I942，但其作用机制仍知之甚少。在这里，我们利用核磁共振光谱映射I942-EPAC 1的相互作用在原子分辨率，并提出了I942部分激动的机制。我们发现I942与EPAC 1的磷酸盐结合盒（PBC）和碱基结合区（BBR）相互作用，类似于环磷酸腺苷（cAMP）。这些结果不仅揭示了I942与cAMP模拟和竞争的分子基础，而且还表明I942的部分激动作用源于其稳定与活性和非活性EPAC 1状态不同的抑制无能激活中间体的能力。I942的作用机制可能有助于EPAC相关疾病的药物设计。
The exchange protein activated by cAMP (EPAC) is a promising drug target for a wide disease range, from neurodegeneration and infections to cancer and cardiovascular conditions. A novel partial agonist of the EPAC isoform 1 (EPAC1), I942, was recently discovered, but its mechanism of action remains poorly understood. Here, we utilize NMR spectroscopy to map the I942-EPAC1 interactions at atomic resolution and propose a mechanism for I942 partial agonism. We found that I942 interacts with the phosphate binding cassette (PBC) and base binding region (BBR) of EPAC1, similar to cyclic adenosine monophosphate (cAMP). These results not only reveal the molecular basis for the I942 vs cAMP mimicry and competition, but also suggest that the partial agonism of I942 arises from its ability to stabilize an inhibition-incompetent activation intermediate distinct from both active and inactive EPAC1 states. The mechanism of action of I942 may facilitate drug design for EPAC-related diseases.
影响因子：
56.9
作者：
Kawasaki, H;Springett, GM;Graybiel, AM
通讯作者：
Graybiel, AM