Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold.
Patricia R FelicianoCatherine L DrennanM Cristina NonatoPublished in: Proceedings of the National Academy of Sciences of the United States of America (2016)
Fumarate hydratases (FHs) are essential metabolic enzymes grouped into two classes. Here, we present the crystal structure of a class I FH, the cytosolic FH from Leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4Fe-4S] cluster. Our 2.05 Å resolution data further reveal a dimeric architecture for this FH that resembles a heart, with each lobe comprised of two domains that are arranged around the active site. Besides the active site, where the substrate S-malate is bound bidentate to the unique iron of the [4Fe-4S] cluster, other binding pockets are found near the dimeric enzyme interface, some of which are occupied by malonate, shown here to be a weak inhibitor of this enzyme. Taken together, these data provide a framework both for investigations of the class I FH catalytic mechanism and for drug design aimed at fighting neglected tropical diseases.
Keyphrases
- electronic health record
- amino acid
- binding protein
- protein protein
- metal organic framework
- big data
- heart failure
- aqueous solution
- climate change
- genome wide
- single molecule
- atrial fibrillation
- emergency department
- small molecule
- data analysis
- machine learning
- adverse drug
- visible light
- dna methylation
- drug induced
- deep learning
- crystal structure
- iron deficiency
- dna binding
- innate immune