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

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 heat 1 , 2 . The activity of UCP1 is activated by endogenous fatty acids and synthetic smal...

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Bibliographic Details
Published in:Nature (London) Vol. 620; no. 7972; pp. 226 - 231
Main Authors: Kang, Yunlu, Chen, Lei
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 03.08.2023
Nature Publishing Group
Subjects:
101/28
2,4-Dinitrophenol
2,4-Dinitrophenol - chemistry
2,4-Dinitrophenol - metabolism
631/45/612/1237
631/535/1258/1259
82/80
82/83
Adenosine triphosphate
Adenosine Triphosphate - chemistry
Adenosine Triphosphate - metabolism
ATP
Binding sites
Cell Membrane - metabolism
Cytosol - metabolism
Electrochemistry
Electron transport
Fatty acids
Fatty Acids - metabolism
Humanities and Social Sciences
Humans
Lipids
multidisciplinary
Nucleotides
Permeability
Protein Conformation
Proteins
Protons
Respiration
Science
Science (multidisciplinary)
Uncoupling protein 1
Uncoupling Protein 1 - chemistry
Uncoupling Protein 1 - metabolism
ISSN:0028-0836, 1476-4687, 1476-4687
Online Access:Get full text
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Summary: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 heat 1 , 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 ATP 3 – 5 . However, the mechanism by which UCP1 binds to these ligands remains unknown. 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 transmembrane helix 2 (TM2) and TM6. ATP binds in 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. Using cryo-electron microscopy, the structures of human UCP1 in the nucleotide-free state, the DNP activator-bound state, and the inhibitory ATP-bound state are resolved, providing details of how purine nucleotides inhibit UCP1.
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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-023-06332-w