引言
人类有机阳离子转运蛋白1(hOCT1),也称为SLC22A1,是肝脏摄取结构多样的内源性和外源性有机阳离子的重要蛋白,影响着代谢和药物的药代动力学。hOCT1已被认为在许多药物的治疗动力学中起着关键作用,使与hOCT1的相互作用成为新药开发和药物相互作用的重要考虑因素。值得注意的是,二甲双胍,作为2型糖尿病的前线药物,是一种突出的hOCT1底物。相反,hOCT1可以被类似醛固酮受体的类固醇类拮抗剂阿利多醇等药物抑制,这需要深入了解hOCT1与药物的相互作用,在新药物治疗的开发中起到至关重要的作用。尽管进行了大量研究,但在分子水平上,hOCT1转运和抑制机制的具体细节仍然难以捉摸。
2024年3月15日,清华大学刘翔宇、陈立功及闫创业共同通讯在
Cell Discovery
(IF 34)在线发表题为“
Structural insights into human organic cation transporter 1 transport and inhibition
”的研究论文,该研究
提出了hOCT1-二甲双胍复合物的冷冻电子
显微镜结构
,显示了三种不同构象状态——向外开放、向外阻塞和向内阻塞,以及部分和完全开放状态下的无底物hOCT1。
该研究还提出了hOCT1与阿利多醇在向外和向内构象状态下的复合物。这些结构提供了关于通过hOCT1进行二甲双胍转运的动态过程以及阿利多醇如何抑制它的机制的原子水平洞察力。此外,该研究确定了一个关键的“YER”基序,对hOCT1的构象灵活性以及可能对其他SLC22家族转运蛋白起作用。总之,该研究显著推进了对hOCT1分子功能的理解,并为设计针对该转运蛋白的新治疗药物奠定了基础框架。
许多药物和内源性分子在细胞和细胞器膜之间的转运是由转运蛋白促进的。
在这些转运蛋白中,有机阳离子转运蛋白OCT1(SLC22A1),作为SLC22家族的成员,在肝脏中表达较多,并于1994年首次被鉴定出来。OCT1已被确定为多种药理学上重要药物的关键肝脏转运蛋白,包括二甲双胍、抗癌药奥沙利铂和
阿片类药物
吗啡。
OCT1还被认为高容量地转运硫胺素,通过调节细胞能量状态来调节肝脏脂肪变性,并作为一种神经递质转运蛋白,控制循环儿茶酚胺水平。
hOCT1的功能影响着许多药物的药代动力学,药物基因组学研究表明,影响hOCT1活性的基因多态性可能改变药物的效果,有时会导致不良反应。
尽管hOCT1是主要的肝脏转运蛋白,但hOCT家族成员hOCT2和hOCT3在肾脏和其他器官系统中也有作用。尽管其序列同源性较高,但OCT1、OCT2和OCT3在组织分布、底物特异性和药理学抑制方面存在明显差异,突显了它们独特的生理作用。
对这些差异的清晰理解对于开发精准医学策略至关重要。
参与hOCT1构象变化的3个关键残基(Credit:
Cell Discovery)
作为主要促进子超家族(MFS)的一部分,hOCT1通过交替进入机制运作,通过转运蛋白构象变化,将底物结合位点交替暴露于膜的两侧。
每个hOCT1转运周期涉及从向外开放到向外阻塞,然后是向内阻塞,最后是向内开放状态的转变。尽管最近通过研究hOCT3的向外构象、OCT1cs和OCT2cs的一致突变来定义了转运机制的进展,但动态的底物转运过程仍然不明确。
为了完全定义转运机制,需要详细的hOCT1转型状态的结构信息。
该研究阐明了hOCT1与二甲双胍复合物的冷冻电子显微镜结构,捕捉了三种关键的构象状态,以及在向内开放状态下的无底物hOCT1。
此外,该研究展示了hOCT1与抑制剂阿利多醇结合的结构,揭示了hOCT1的转运和抑制的分子机制。
|探索君
排版|探索君
文章来源|“iNature”
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