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Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy.

Pettinati I, Brem J, McDonough MA, Schofield CJ - Hum. Mol. Genet. (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.

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hETHE1 active site and comparison of the hETHE1 crystal structure with other MBL-fold enzymes. (A) Wall-eyed stereoview of the iron binding and active site residues of hETHE1 with representative electron density (3.0 σ mFo-DFc OMIT; green mesh) for side chains of His79 (Nϵ2 to Fe: 2.3 Å), His135 (Nϵ2 to Fe: 2.22 Å), Asp 154 (Oδ2 to Fe: 2.05 Å) and the three water molecules (red spheres) which coordinate (black dashed lines) to the iron (orange sphere). (B) Wall-eyed stereoview of superimposed active site residues from hETHE1 (cyan) and BcII from Bacillus cereus (PDB ID: 1BVT) (orange). The zinc and iron ions are in grey and dark red, respectively. The zinc ions in the Zn1 and Zn2 sites are labelled (17). There is relatively strong conservation in iron-binding residues by ETHE1 and at the Zn1 site of glyoxalase II; although the Zn2 binding site residues are conserved in hETHE1, they do not bind the iron ion. (C) Wall-eyed stereoview of the superimposed active site residues from hETHE1 (cyan) and human glyoxalase II (PDB ID: 1QH3/5) (green). Note. There are more differences between hETHE1 and BcII than between hETHE1 and glyoxalase II.
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DDV007F6: hETHE1 active site and comparison of the hETHE1 crystal structure with other MBL-fold enzymes. (A) Wall-eyed stereoview of the iron binding and active site residues of hETHE1 with representative electron density (3.0 σ mFo-DFc OMIT; green mesh) for side chains of His79 (Nϵ2 to Fe: 2.3 Å), His135 (Nϵ2 to Fe: 2.22 Å), Asp 154 (Oδ2 to Fe: 2.05 Å) and the three water molecules (red spheres) which coordinate (black dashed lines) to the iron (orange sphere). (B) Wall-eyed stereoview of superimposed active site residues from hETHE1 (cyan) and BcII from Bacillus cereus (PDB ID: 1BVT) (orange). The zinc and iron ions are in grey and dark red, respectively. The zinc ions in the Zn1 and Zn2 sites are labelled (17). There is relatively strong conservation in iron-binding residues by ETHE1 and at the Zn1 site of glyoxalase II; although the Zn2 binding site residues are conserved in hETHE1, they do not bind the iron ion. (C) Wall-eyed stereoview of the superimposed active site residues from hETHE1 (cyan) and human glyoxalase II (PDB ID: 1QH3/5) (green). Note. There are more differences between hETHE1 and BcII than between hETHE1 and glyoxalase II.

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.


Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy.

Pettinati I, Brem J, McDonough MA, Schofield CJ - Hum. Mol. Genet. (2015)

hETHE1 active site and comparison of the hETHE1 crystal structure with other MBL-fold enzymes. (A) Wall-eyed stereoview of the iron binding and active site residues of hETHE1 with representative electron density (3.0 σ mFo-DFc OMIT; green mesh) for side chains of His79 (Nϵ2 to Fe: 2.3 Å), His135 (Nϵ2 to Fe: 2.22 Å), Asp 154 (Oδ2 to Fe: 2.05 Å) and the three water molecules (red spheres) which coordinate (black dashed lines) to the iron (orange sphere). (B) Wall-eyed stereoview of superimposed active site residues from hETHE1 (cyan) and BcII from Bacillus cereus (PDB ID: 1BVT) (orange). The zinc and iron ions are in grey and dark red, respectively. The zinc ions in the Zn1 and Zn2 sites are labelled (17). There is relatively strong conservation in iron-binding residues by ETHE1 and at the Zn1 site of glyoxalase II; although the Zn2 binding site residues are conserved in hETHE1, they do not bind the iron ion. (C) Wall-eyed stereoview of the superimposed active site residues from hETHE1 (cyan) and human glyoxalase II (PDB ID: 1QH3/5) (green). Note. There are more differences between hETHE1 and BcII than between hETHE1 and glyoxalase II.
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DDV007F6: hETHE1 active site and comparison of the hETHE1 crystal structure with other MBL-fold enzymes. (A) Wall-eyed stereoview of the iron binding and active site residues of hETHE1 with representative electron density (3.0 σ mFo-DFc OMIT; green mesh) for side chains of His79 (Nϵ2 to Fe: 2.3 Å), His135 (Nϵ2 to Fe: 2.22 Å), Asp 154 (Oδ2 to Fe: 2.05 Å) and the three water molecules (red spheres) which coordinate (black dashed lines) to the iron (orange sphere). (B) Wall-eyed stereoview of superimposed active site residues from hETHE1 (cyan) and BcII from Bacillus cereus (PDB ID: 1BVT) (orange). The zinc and iron ions are in grey and dark red, respectively. The zinc ions in the Zn1 and Zn2 sites are labelled (17). There is relatively strong conservation in iron-binding residues by ETHE1 and at the Zn1 site of glyoxalase II; although the Zn2 binding site residues are conserved in hETHE1, they do not bind the iron ion. (C) Wall-eyed stereoview of the superimposed active site residues from hETHE1 (cyan) and human glyoxalase II (PDB ID: 1QH3/5) (green). Note. There are more differences between hETHE1 and BcII than between hETHE1 and glyoxalase II.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.

Show MeSH
Related in: MedlinePlus