4CHL

Human Ethylmalonic Encephalopathy Protein 1 (hETHE1)

Summary for 4CHL

• Entry DOI: 10.2210/pdb4chl/pdb
• Descriptor: PERSULFIDE DIOXYGENASE ETHE1, MITOCHONDRIAL, FE (III) ION (3 entities in total)
• Functional Keywords: oxidoreductase, sulfide detoxification, glyoxalase ii family
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : O95571
• Total number of polymer chains: 2
• Total formula weight: 52469.42

Authors

Pettinati, I.,Brem, J.,McDonough, M.A.,Schofield, C.J. (deposition date: 2013-12-03, release date: 2014-12-17, Last modification date: 2024-11-20)

Primary citation

Pettinati, I.,Brem, J.,McDonough, M.A.,Schofield, C.J.
Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy.
Hum. Mol. Genet., 24:2458-2469, 2015

PubMed Abstract: The ethylmalonic encephalopathy protein 1 (ETHE1) catalyses the oxygen-dependent oxidation of glutathione persulfide (GSSH) to give persulfite and glutathione. Mutations to the hETHE1 gene compromise sulfide metabolism leading to the genetic disease ethylmalonic encephalopathy. hETHE1 is a mono-iron binding member of the metallo-β-lactamase (MBL) fold superfamily. We report crystallographic analysis of hETHE1 in complex with iron to 2.6 Å resolution. hETHE1 contains an αββα MBL-fold, which supports metal-binding by the side chains of an aspartate and two histidine residues; three water molecules complete octahedral coordination of the iron. The iron binding hETHE1 enzyme is related to the 'classical' di-zinc binding MBL hydrolases involved in antibiotic resistance, but has distinctive features. The histidine and aspartate residues involved in iron-binding in ETHE1, occupy similar positions to those observed across both the zinc 1 and zinc 2 binding sites in classical MBLs. The active site of hETHE1 is very similar to an ETHE1-like enzyme from Arabidopsis thaliana (60% sequence identity). A channel leading to the active site is sufficiently large to accommodate a GSSH substrate. Some of the observed hETHE1 clinical mutations cluster in the active site region. The structure will serve as a basis for detailed functional and mechanistic studies on ETHE1 and will be useful in the development of selective MBL inhibitors.

PubMed: 25596185
DOI: 10.1093/hmg/ddv007

Experimental method

X-RAY DIFFRACTION (2.61 Å)