4ZUL

Structure ALDH7A1 complexed with alpha-aminoadipate

4ZUL の概要

• エントリーDOI: 10.2210/pdb4zul/pdb
• 関連するPDBエントリー: 4ZUK
• 分子名称: Alpha-aminoadipic semialdehyde dehydrogenase, TRIETHYLENE GLYCOL, 2-AMINOHEXANEDIOIC ACID, ... (5 entities in total)
• 機能のキーワード: aldehyde dehydrogenase, nad, oxidoreductase, lysine catabolism
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Mitochondrion . Isoform 2: Cytoplasm, cytosol: P49419
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 447691.85

構造登録者

Luo, M.,Tanner, J.J. (登録日: 2015-05-16, 公開日: 2015-08-26, 最終更新日: 2023-11-15)

主引用文献

Luo, M.,Tanner, J.J.
Structural Basis of Substrate Recognition by Aldehyde Dehydrogenase 7A1.
Biochemistry, 54:5513-5522, 2015

PubMed Abstract: Aldehyde dehydrogenase 7A1 (ALDH7A1) is part of lysine catabolism and catalyzes the NAD(+)-dependent oxidation of α-aminoadipate semialdehyde to α-aminoadipate. Herein, we describe a structural study of human ALDH7A1 focused on substrate recognition. Five crystal structures and small-angle X-ray scattering data are reported, including the first crystal structure of any ALDH7 family member complexed with α-aminoadipate. The product binds with the ε-carboxylate in the oxyanion hole, the aliphatic chain packed into an aromatic box, and the distal end of the product anchored by electrostatic interactions with five conserved residues. This binding mode resembles that of glutamate bound to the proline catabolic enzyme ALDH4A1. Analysis of ALDH7A1 and ALDH4A1 structures suggests key interactions that underlie substrate discrimination. Structures of apo ALDH7A1 reveal dramatic conformational differences from the product complex. Product binding is associated with a 16 Å movement of the C-terminus into the active site, which stabilizes the active conformation of the aldehyde substrate anchor loop. The fact that the C-terminus is part of the active site was hitherto unknown. Interestingly, the C-terminus and aldehyde anchor loop are disordered in a new tetragonal crystal form of the apoenzyme, implying that these parts of the enzyme are highly flexible. Our results suggest that the active site of ALDH7A1 is disassembled when the aldehyde site is vacant, and the C-terminus is a mobile element that forms quaternary structural interactions that aid aldehyde binding. These results are relevant to the c.1512delG genetic deletion associated with pyridoxine-dependent epilepsy, which alters the C-terminus of ALDH7A1.

PubMed: 26260980
DOI: 10.1021/acs.biochem.5b00754

実験手法

X-RAY DIFFRACTION (1.76 Å)