8W7F

Structure of Drosophila melanogaster L-2-hydroxyglutarate dehydrogenase bound with FAD and a sulfate ion

8W7F の概要

• エントリーDOI: 10.2210/pdb8w7f/pdb
• 分子名称: FI05204p, SULFATE ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: l-2-hydroxyglutarate dehydrogenase, l2hgdh, dehydrogenase, oxidoreductase
• 由来する生物種: Drosophila melanogaster (fruit fly)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 189244.21

構造登録者

Yang, J.,Chen, X.,Jin, S.,Ding, J. (登録日: 2023-08-30, 公開日: 2023-11-29, 最終更新日: 2024-11-20)

主引用文献

Yang, J.,Chen, X.,Jin, S.,Ding, J.
Structure and biochemical characterization of l-2-hydroxyglutarate dehydrogenase and its role in the pathogenesis of l-2-hydroxyglutaric aciduria.
J.Biol.Chem., 300:105491-105491, 2023

PubMed Abstract: l-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial membrane-associated metabolic enzyme, which catalyzes the oxidation of l-2-hydroxyglutarate (l-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH lead to abnormal accumulation of l-2-HG, which causes a neurometabolic disorder named l-2-hydroxyglutaric aciduria (l-2-HGA). Here, we report the crystal structures of Drosophila melanogaster L2HGDH (dmL2HGDH) in FAD-bound form and in complex with FAD and 2-OG and show that dmL2HGDH exhibits high activity and substrate specificity for l-2-HG. dmL2HGDH consists of an FAD-binding domain and a substrate-binding domain, and the active site is located at the interface of the two domains with 2-OG binding to the re-face of the isoalloxazine moiety of FAD. Mutagenesis and activity assay confirmed the functional roles of key residues involved in the substrate binding and catalytic reaction and showed that most of the mutations of dmL2HGDH equivalent to l-2-HGA-associated mutations of human L2HGDH led to complete loss of the activity. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of L2HGDH and provide insights into the functional roles of human L2HGDH mutations in the pathogeneses of l-2-HGA.

PubMed: 37995940
DOI: 10.1016/j.jbc.2023.105491

実験手法

X-RAY DIFFRACTION (2.299 Å)