8UY2

Methylenetetrahydrofolate reductase from Chaetomium thermophilum DSM 1495, AdoMet-bound, Inhibited (T) State

8UY2 の概要

• エントリーDOI: 10.2210/pdb8uy2/pdb
• 分子名称: Methylenetetrahydrofolate reductase-like protein, FLAVIN-ADENINE DINUCLEOTIDE, S-ADENOSYLMETHIONINE, ... (8 entities in total)
• 機能のキーワード: methylenetetrahydrofolate reductase, nadph activity, oxidoreductase activity, acting on the ch-nh group of donors, nad or nadp as acceptor cobalamin binding, one-carbon metabolism, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Thermochaetoides thermophila DSM 1495
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 288663.74

構造登録者

Yamada, K.,Mendoza, J.,Koutmos, M. (登録日: 2023-11-12, 公開日: 2024-06-19, 最終更新日: 2024-07-03)

主引用文献

Yamada, K.,Mendoza, J.,Koutmos, M.
Structural basis of S-adenosylmethionine-dependent allosteric transition from active to inactive states in methylenetetrahydrofolate reductase.
Nat Commun, 15:5167-5167, 2024

PubMed Abstract: Methylenetetrahydrofolate reductase (MTHFR) is a pivotal flavoprotein connecting the folate and methionine methyl cycles, catalyzing the conversion of methylenetetrahydrofolate to methyltetrahydrofolate. Human MTHFR (hMTHFR) undergoes elaborate allosteric regulation involving protein phosphorylation and S-adenosylmethionine (AdoMet)-dependent inhibition, though other factors such as subunit orientation and FAD status remain understudied due to the lack of a functional structural model. Here, we report crystal structures of Chaetomium thermophilum MTHFR (cMTHFR) in both active (R) and inhibited (T) states. We reveal FAD occlusion by Tyr361 in the T-state, which prevents substrate interaction. Remarkably, the inhibited form of cMTHFR accommodates two AdoMet molecules per subunit. In addition, we conducted a detailed investigation of the phosphorylation sites in hMTHFR, three of which were previously unidentified. Based on the structural framework provided by our cMTHFR model, we propose a possible mechanism to explain the allosteric structural transition of MTHFR, including the impact of phosphorylation on AdoMet-dependent inhibition.

PubMed: 38886362
DOI: 10.1038/s41467-024-49327-5

実験手法

X-RAY DIFFRACTION (2.83 Å)