6yyw

Aspartyl/Asparaginyl beta-hydroxylase (AspH) oxygenase and TPR domains in complex with manganese, 2-oxoglutarate, and factor X substrate peptide fragment(39mer-4Ser)

spinqualitylabelsall models 6yyw, resolution 2.27Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6yyw is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.27Å Ligands: AKG, MN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 2-Oxoglutarate (2OG) is involved in biological processes including oxidations catalyzed by 2OG oxygenases for which it is a cosubstrate. Eukaryotic 2OG oxygenases have roles in collagen biosynthesis, lipid metabolism, DNA/RNA modification, transcriptional regulation, and the hypoxic response. Aspartate/asparagine-beta-hydroxylase (AspH) is a human 2OG oxygenase catalyzing post-translational hydroxylation of Asp/Asn-residues in epidermal growth factor-like domains (EGFDs) in the endoplasmic reticulum. AspH is of chemical interest, because its Fe(ii) cofactor is complexed by two rather than the typical three residues. AspH is upregulated in hypoxia and is a prognostic marker on the surface of cancer cells. We describe studies on how derivatives of its natural 2OG cosubstrate modulate AspH activity. An efficient synthesis of C3- and/or C4-substituted 2OG derivatives, proceeding via cyanosulfur ylid intermediates, is reported. Mass spectrometry-based AspH assays with >30 2OG derivatives reveal that some efficiently inhibit AspH via competing with 2OG as evidenced by crystallographic and solution analyses. Other 2OG derivatives can substitute for 2OG enabling substrate hydroxylation. The results show that subtle changes, e.g. methyl- to ethyl-substitution, can significantly alter the balance between catalysis and inhibition. 3-Methyl-2OG, a natural product present in human nutrition, was the most efficient alternative cosubstrate identified; crystallographic analyses reveal the binding mode of (R)-3-methyl-2OG and other 2OG derivatives to AspH and inform on the balance between turnover and inhibition. The results will enable the use of 2OG derivatives as mechanistic probes for other 2OG utilizing enzymes and suggest 2-oxoacids other than 2OG may be employed by some 2OG oxygenases in vivo. Synthesis of 2-oxoglutarate derivatives and their evaluation as cosubstrates and inhibitors of human aspartate/asparagine-beta-hydroxylase.,Brewitz L, Nakashima Y, Schofield CJ Chem Sci. 2020 Dec 7;12(4):1327-1342. doi: 10.1039/d0sc04301j. PMID:34163896 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Hydroxylases 3D structures

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