8RE6

Aspartyl/Asparaginyl beta-hydroxylase (AspH) R735Q variant in complex with Mn, 2-oxoglutarate and a Factor X derived peptide fragment

8RE6 の概要

• エントリーDOI: 10.2210/pdb8re6/pdb
• 分子名称: Aspartyl/asparaginyl beta-hydroxylase, Coagulation factor X, MANGANESE (II) ION, ... (5 entities in total)
• 機能のキーワード: asph, aspartyl/asparaginyl beta-hydroxylase, 2-oxoglutarate, 2og, alpha-ketoglutarate, substrate analogues, oxidoreductase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 55555.81

構造登録者

Brasnett, A.,Hou, C.,Rabe, P.,Brewitz, L.,Schofield, C.J. (登録日: 2023-12-10, 公開日: 2024-12-18, 最終更新日: 2025-12-24)

主引用文献

Hou, C.X.,Brasnett, A.,Rabe, P.,Schofield, C.J.,Brewitz, L.
Structural and functional consequences of aspartate/asparagine-beta-hydroxylase variants causing Traboulsi Syndrome.
J.Biol.Chem., :111008-111008, 2025

PubMed Abstract: Traboulsi Syndrome is an autosomal recessive hereditary disease associated with developmental defects, in particular of the ocular system. Single nucleotide polymorphisms affecting the ASPH gene, which encodes for the 2-oxoglutarate (2OG)-dependent oxygenase aspartate/asparagine-β-hydroxylase (AspH), are associated with Traboulsi Syndrome. AspH catalyzes hydroxylations of conserved aspartate/asparagine residues in epidermal growth factor-like domain (EGFD) proteins. We report studies on the clinically-observed Traboulsi Syndrome-associated R688Q, R735Q, and R735W AspH variants. The results reveal that pathogenic active site substitutions substantially reduce, though do not ablate, EGFD hydroxylase activity compared to wildtype AspH. They imply that efficient AspH catalyzed EGFD hydroxylation is important during human development. Crystallographic studies reveal conservation of the overall AspH fold, but that the preferred conformations of 2OG in complex with the R735Q and R735W AspH variants differ from that with wildtype AspH. Screening of potential 2OG cosubstrate substitutes reveals certain 2-oxoacids, including naturally present metabolites, manifest enhanced catalytic efficiency of Traboulsi Syndrome-associated AspH variants compared to 2OG. The results thus provide proof-of-principle for a therapeutic strategy involving rescue of impaired activities of pathogenic active site AspH variants by use of 2-oxoacids, or 2-oxoacid precursors, other than 2OG.

PubMed: 41354343
DOI: 10.1016/j.jbc.2025.111008

実験手法

X-RAY DIFFRACTION (1.92 Å)