小柯机器人

北京大学陈雷研究组揭示DNP和嘌呤核苷酸与UCP1结合的结构基础。该项研究成果于2023年6月19日在线发表在《自然》杂志上。

研究人员表示，解偶联蛋白1（UCP1）通过线粒体内膜传导质子，使线粒体呼吸与ATP生成脱钩，从而将质子的电化学梯度转化为热量。UCP1的活性被内源性脂肪酸和合成小分子，如2,4-二硝基酚（DNP）激活，并被嘌呤核苷酸，如ATP抑制。然而，UCP1与这些配体结合的机制仍然难以确定。

研究人员展示了人类UCP1在无核苷酸状态、与DNP结合状态和与ATP结合状态的结构。这些结构显示，UCP1的中央空腔是向细胞膜一侧开放的。DNP在空腔内结合，并与TM2和TM6接触。ATP也在同一空腔内结合，并引起TM2的构象变化，同时UCP1的TM1、TM4、TM5和TM6向内弯曲，导致UCP1的结构更加紧凑。ATP的结合位点与DNP的结合位点重叠，表明ATP竞争性地阻断了DNP的功能参与，导致UCP1的质子传导活性受到抑制。

附：英文原文

Title: Structural basis for the binding of DNP and purine nucleotides onto UCP1

Author: Kang, Yunlu, Chen, Lei

Issue&Volume: 2023-06-19

Abstract: Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat1,2. The activity of UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP3-5. However, the mechanism by which UCP1 binds these ligands remains elusive. Here, we present the structures of human UCP1 in the nucleotide-free state, the DNP-bound state, and the ATP-bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with TM2 and TM6. ATP also binds inside the same cavity and induces conformational changes in TM2, together with the inward bending of TM1, TM4, TM5, and TM6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps with that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1.

DOI: 10.1038/s41586-023-06332-w

Source: https://www.nature.com/articles/s41586-023-06332-w

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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