Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy.
Bottom Line: 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.
Affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.Show MeSH
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Mentions: Comparison of hETHE1 active site with those of the Class B1, B2 and B3 prokaryotic MBLs. (A) Wall-eyed stereoviews of superimposed active site residues from the Class B1 MBL BcII from Bacillus cereus (PDB ID: 1BVT) (orange), the Class B2 MBL CphA from Aeromonas hydrophila (PDB ID: 3F9O) (pink) and the Class B3 MBL FEZ-1 from Legionella gormanii (PDB ID: 1K07) (blue). The standard BBL numbering system for MBLs is used (17). Residues present in all the three active sites are numbered in black, zinc ions are in light-orange (BcII), light-pink (CphA) and light-blue (FEZ-1). Note that the zinc-ligating residue His121 is only present in the Class B3 FEZ-1, whereas Cys221 is absent in the FEZ-1 B3 MBL compared with the Class B1 and B2 MBLs. The FEZ-1 active site residue composition is most similar to that of the hMBLs, despite the latter apparently displaying closer similarity with the Class B1 MBLs from an overall structural perspective (see Fig. 6). (B) Wall-eyed stereoview of the hETHE1 active site residues. The hETHE1 residue numbering is in blue and based on the enzyme sequence; BBL numbering is shown below in black. Note that in superimposition of hETHE1 with BcII (Fig. 6C), His79ETHE1 (His116BBL) does not correlate with His116BBL of BcII, but with His118BBL showing a different organization of conserved residues in their active sites. Note that the side chains of His84ETHE1 (His121BBL) and FEZ-1 His121BBL are observed in different orientations in their respective active sites, probably because His121BBL of FEZ-1 is involved in an additional metal binding (zinc 2 site), which is not observed in hETHE1.
Affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.