9DXU

Crystal structure of cobalt-incorporated human 2-aminoethanethiol (aka cysteamine) dioxygenase (ADO) variant C18S/C239S in complex with CP6

9DXU の概要

• エントリーDOI: 10.2210/pdb9dxu/pdb
• 分子名称: 2-aminoethanethiol dioxygenase, CP6, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (7 entities in total)
• 機能のキーワード: oxygen-sensor, thiol dioxygenase, 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: 32645.08

構造登録者

Jiramongkol, Y.,Patel, K.,White, M.D. (登録日: 2024-10-11, 公開日: 2025-06-04)

主引用文献

Jiramongkol, Y.,Patel, K.,Johansen-Leete, J.,Maxwell, J.W.C.,Chang, Y.,Du, J.J.,Passioura, T.,Cook, K.M.,Payne, R.J.,White, M.D.
An mRNA-display derived cyclic peptide scaffold reveals the substrate binding interactions of an N-terminal cysteine oxidase.
Nat Commun, 16:4761-4761, 2025

PubMed Abstract: N-terminal cysteine oxidases (NCOs) act as enzymatic oxygen (O) sensors, coordinating cellular changes to hypoxia in animals and plants. They regulate the O-dependent stability of proteins bearing an N-terminal cysteine residue through the N-degron pathway. Despite their important role in hypoxic adaptation, which renders them potential therapeutic and agrichemical targets, structural information on NCO substrate binding remains elusive. To overcome this challenge, we employed a unique strategy by which a cyclic peptide inhibitor of the mammalian NCO, 2-aminoethanethiol dioxygenase (ADO), was identified by mRNA display and used as a scaffold to graft substrate moieties. This allowed the determination of two substrate analogue-bound crystal structures of ADO. Key binding interactions were revealed, including bidentate coordination of the N-terminal residue at the metal cofactor. Subsequent structure guided mutagenesis identified aspartate-206 as an essential catalytic residue, playing a role in reactive oxygen intermediate orientation or stabilisation. These findings provide fundamental information on ADO substrate interactions, which can elucidate enzyme mechanism and act as a platform for chemical discovery.

PubMed: 40404614
DOI: 10.1038/s41467-025-59960-3

実験手法

X-RAY DIFFRACTION (1.74 Å)