Abstract
MitoNEET (gene cisd1) is a mitochondrial outer membrane [2Fe-2S] protein and is a potential drug target in several metabolic diseases. Previous studies have demonstrated that mitoNEET functions as a redox-active and pH-sensing protein that regulates mitochondrial metabolism, although the structural basis of the potential drug binding site(s) remains elusive. Here we report the crystal structure of the soluble domain of human mitoNEET with a sulfonamide ligand, furosemide. Exploration of the high-resolution crystal structure is used to design mitoNEET binding molecules in a pilot study of molecular probes for use in future development of mitochondrial targeted therapies for a wide variety of metabolic diseases, including obesity, diabetes and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.
Highlights
ObjectivesOur goal was to identify a compound that could be used to achieve a co-crystal structure with mitoNEET, as the glitazones tended to precipitate out of solution failing to co-crystalize
Probe 2.7 μM [Probe], μM Cl O S NH2 R–NH2 Cl CO2HEt3N, DME μW, 150 °C R = CH3(CH2)n2a n = 2 2b n = 3 2c n = 4 2d n = 52e n = 6 2f n = 7 R N H
Based on the published literature, mitoNEET represents a potential drug target for the development of compounds to treat a variety of metabolic diseases[6,7,14]
Summary
Our goal was to identify a compound that could be used to achieve a co-crystal structure with mitoNEET, as the glitazones tended to precipitate out of solution failing to co-crystalize
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