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Structural Determinants of the γ-8 TARP Dependent AMPA Receptor Antagonist
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2017-09-05 00:00:00 , DOI: 10.1021/acschemneuro.7b00186
Matthew R. Lee 1 , Kevin M. Gardinier 2 , Douglas L. Gernert 2 , Douglas A. Schober 2 , Rebecca A. Wright 2 , He Wang 2 , Yuewei Qian 2 , Jeffrey M. Witkin 2 , Eric S. Nisenbaum 2 , Akihiko S. Kato 2
Affiliation  

The forebrain specific AMPA receptor antagonist, LY3130481/CERC-611, which selectively antagonizes the AMPA receptors associated with TARP γ-8, an auxiliary subunit enriched in the forebrain, has potent antiepileptic activities without motor side effects. We designated the compounds with such activities as γ-8 TARP dependent AMPA receptor antagonists (γ-8 TDAAs). In this work, we further investigated the mechanisms of action using a radiolabeled γ-8 TDAA and ternary structural modeling with mutational validations to characterize the LY3130481 binding to γ-8. The radioligand binding to the cells heterologously expressing GluA1 and/or γ-8 revealed that γ-8 TDAAs binds to γ-8 alone without AMPA receptors. Homology modeling of γ-8, based on the crystal structures of a distant TARP homologue, murine claudin 19, in conjunction with knowledge of two γ-8 residues previously identified as critical for the LY3130481 TARP-dependent selectivity provided the basis for a binding mode prediction. This allowed further rational mutational studies for characterization of the structural determinants in TARP γ-8 for LY3130481 activities, both thermodynamically as well as kinetically.

中文翻译:

γ-8TARP依赖性AMPA受体拮抗剂的结构决定因素

前脑特异性AMPA受体拮抗剂LY3130481 / CERC-611可选择性拮抗与富含前脑的辅助亚基TARPγ-8相关的AMPA受体,具有有效的抗癫痫活性,且无运动副作用。我们将具有此类活性的化合物指定为γ-8TARP依赖性AMPA受体拮抗剂(γ-8TDAAs)。在这项工作中,我们进一步研究了使用放射性标记的γ-8TDAA的作用机制和具有突变验证的三元结构模型,以表征LY3130481与γ-8的结合。放射性配体与异源表达GluA1和/或γ-8的细胞结合,表明γ-8TDAAs仅与γ-8结合而没有AMPA受体。基于遥远的TARP同源物鼠claudin 19的晶体结构对γ-8进行同源性建模,结合先前鉴定为对LY3130481 TARP依赖的选择性至关重要的两个γ-8残基的知识,为预测结合模式提供了基础。这允许进行进一步的合理的突变研究,以表征TARPγ-8中LY3130481活性的结构决定簇(无论是热力学还是动力学的)。
更新日期:2017-09-05
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