Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps.

IF 3.5 3区 医学 Q2 CHEMISTRY, MULTIDISCIPLINARY Pharmaceutical Research Pub Date : 2024-11-01 DOI:10.1007/s11095-024-03786-z
Alper Karagöl, Taner Karagöl, Mengke Li, Shuguang Zhang
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Abstract

Objective: Glutamate transporters play a key role in central nervous system physiology by maintaining excitatory neurotransmitter homeostasis. Biological assemblies of the transporters, consisting of cyclic homotrimers, emerge as a crucial aspect of glutamate transporter modulation. Hence targeting heteromerization promises an effective approach for modulator design. On the other hand, the dynamic nature of transcription allows for the generation of transporter isoforms in structurally distinct manners.

Methods: The potential isoforms were identified through the analysis of computationally generated gene-centric isoform maps. The conserved features of isoform sequences were revealed by computational chemistry methods and subsequent structural analysis of AlphaFold2 predictions. Truncated isoforms were further subjected to a wide range of docking analyses, 50ns molecular dynamics simulations, and evolutionary coupling analyses.

Results: Energetic landscapes of isoform-canonical transporter complexes suggested an inhibitory potential of truncated isoforms on glutamate transporter bio-assembly. Moreover, isoforms that mimic the trimerization domain (in particular, TM2 helices) exhibited stronger interactions with canonical transporters, underscoring the role of transmembrane helices in isoform interactions. Additionally, self-assembly dynamics observed in truncated isoforms mimicking canonical TM5 helices indicate a potential protective role against unwanted interactions with canonical transporters.

Conclusion: Our computational studies on glutamate transporters offer insights into the roles of alternative splicing on protein interactions and identifies potential drug targets for physiological or pathological processes.

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通过对以基因为中心的同工酶图谱进行计算分析发现的截短同工酶对谷氨酸转运体寡聚化的抑制潜能
目的谷氨酸转运体通过维持兴奋性神经递质的平衡,在中枢神经系统生理学中发挥着关键作用。由环状同源三聚体组成的转运体生物组装是谷氨酸转运体调节的一个重要方面。因此,以异构化为目标有望成为设计调节剂的有效方法。另一方面,转录的动态性质允许以结构不同的方式产生转运体异构体:方法:通过分析计算生成的以基因为中心的异构体图谱,确定了潜在的异构体。通过计算化学方法和随后的 AlphaFold2 预测结构分析,揭示了异构体序列的保守特征。对截短的同工酶进一步进行了广泛的对接分析、50ns分子动力学模拟和进化耦合分析:结果:异构体-典型转运体复合物的能量图谱表明,截短异构体对谷氨酸转运体的生物组装具有抑制潜力。此外,模拟三聚化结构域的异构体(尤其是 TM2 螺旋)与典型转运体的相互作用更强,这突出了跨膜螺旋在异构体相互作用中的作用。此外,在模仿典型 TM5 螺旋的截短异构体中观察到的自组装动力学表明,该异构体具有潜在的保护作用,可防止与典型转运体发生不必要的相互作用:我们对谷氨酸转运体的计算研究深入揭示了替代剪接在蛋白质相互作用中的作用,并为生理或病理过程确定了潜在的药物靶点。
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来源期刊
Pharmaceutical Research
Pharmaceutical Research 医学-化学综合
CiteScore
6.60
自引率
5.40%
发文量
276
审稿时长
3.4 months
期刊介绍: Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.
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