Crystal structure of the mitochondrial protein mitoNEET bound to a benze-sulfonide ligand.
Werner J GeldenhuysTimothy E LongPushkar SaralkarToshio IwasakiRaisa A A NuñezRajesh R NairMary E KonkleMichael A MenzeMark V PintiJohn M HollanderLori A HazlehurstAaron R RobartPublished in: Communications chemistry (2019)
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.
Keyphrases
- oxidative stress
- crystal structure
- high resolution
- type diabetes
- structural basis
- protein protein
- binding protein
- endothelial cells
- small molecule
- metabolic syndrome
- cardiovascular disease
- amino acid
- mass spectrometry
- physical activity
- dna methylation
- adipose tissue
- human health
- weight gain
- skeletal muscle
- current status
- transcription factor
- body mass index
- living cells
- induced pluripotent stem cells