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Identification of the benztropine analog [125I]GA II 34 binding site on the human dopamine transporter.
Neurochemistry international ( IF 4.4 ) Pub Date : 2018-08-17 , DOI: 10.1016/j.neuint.2018.08.008
Michael J Tomlinson 1 , Danielle Krout 1 , Akula Bala Pramod 1 , John R Lever 2 , Amy Hauck Newman 3 , L Keith Henry 1 , Roxanne A Vaughan 1
Affiliation  

The dopamine transporter (DAT) is a neuronal membrane protein that is responsible for reuptake of dopamine (DA) from the synapse and functions as a major determinant in control of DA neurotransmission. Cocaine and many psychostimulant drugs bind to DAT and block reuptake, inducing DA overflow that forms the neurochemical basis for euphoria and addiction. Paradoxically, however, some ligands such as benztropine (BZT) bind to DAT and inhibit reuptake but do not produce these effects, and it has been hypothesized that differential mechanisms of binding may stabilize specific transporter conformations that affect downstream neurochemical or behavioral outcomes. To investigate the binding mechanisms of BZT on DAT we used the photoaffinity BZT analog [125I]N-[n-butyl-4-(4‴-azido-3‴-iodophenyl)]-4',4″-difluoro-3α-(diphenylmethoxy)tropane ([125I]GA II 34) to identify the site of cross-linking and predict the binding pose relative to that of previously-examined cocaine photoaffinity analogs. Biochemical findings show that adduction of [125I]GA II 34 occurs at residues Asp79 or Leu80 in TM1, with molecular modeling supporting adduction to Leu80 and a pharmacophore pose in the central S1 site similar to that of cocaine and cocaine analogs. Substituted cysteine accessibility method protection analyses verified these findings, but identified some differences in structural stabilization relative to cocaine that may relate to BZT neurochemical outcomes.

中文翻译:

鉴定人多巴胺转运蛋白上的苄索品类似物[125I] GA II 34结合位点。

多巴胺转运蛋白(DAT)是一种神经元膜蛋白,负责突触中多巴胺(DA)的再摄取,并且是控制DA神经传递的主要决定因素。可卡因和许多刺激性药物与DAT结合并阻止再摄取,诱导DA溢出,从而形成欣快和成瘾的神经化学基础。然而,自相矛盾的是,某些配体(例如苯甲平)(BZT)与DAT结合并抑制了再摄取,但不会产生这些作用,并且据推测,结合的不同机制可能稳定了影响下游神经化学或行为结果的特定转运蛋白构象。为了研究BZT对DAT的结合机制,我们使用了光亲和力的BZT类似物[125I] N- [n-丁基-4-(4′-叠氮基-3′-碘苯基)]-4',4″-二氟-3α-(二苯基甲氧基)托烷([125I] GA II 34)来确定交联位点,并预测相对于先前可卡因光亲和类似物的结合姿势。生化发现表明[125I] GA II 34的加成发生在TM1的Asp79或Leu80残基上,分子模型支持与可卡因和可卡因类似物相似的加成作用到Leu80和中心S1位上的药效团。替代的半胱氨酸可及性方法保护性分析验证了这些发现,但确定了相对于可卡因的结构稳定方面的某些差异,这可能与BZT神经化学结果有关。生化发现表明[125I] GA II 34的加成发生在TM1的Asp79或Leu80残基上,分子模型支持与可卡因和可卡因类似物相似的加成作用到Leu80和中心S1位上的药效团。替代的半胱氨酸可及性方法保护性分析验证了这些发现,但确定了相对于可卡因的结构稳定方面的某些差异,这可能与BZT神经化学结果有关。生化发现表明,[125I] GA II 34的加成发生在TM1的Asp79或Leu80残基上,分子模型支持与可卡因和可卡因类似物相似的加成作用到Leu80以及中心S1位点上的药效团。替代的半胱氨酸可及性方法保护性分析验证了这些发现,但确定了相对于可卡因的结构稳定方面的某些差异,这可能与BZT神经化学结果有关。
更新日期:2018-08-17
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