8QA4

MTHFR + SAH symmetric dis-inhibited state

8QA4 の概要

• エントリーDOI: 10.2210/pdb8qa4/pdb
• EMDBエントリー: 18298
• 分子名称: Methylenetetrahydrofolate reductase (NADPH), S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total)
• 機能のキーワード: dis-inhibited, allosteric, folate, s-adenosylhomocysteine, flavoprotein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 151691.21

構造登録者

Blomgren, L.K.M.,Yue, W.W.,Froese, D.S.,McCorvie, T.J. (登録日: 2023-08-22, 公開日: 2023-11-08, 最終更新日: 2025-12-10)

主引用文献

Blomgren, L.K.M.,Huber, M.,Mackinnon, S.R.,Burer, C.,Basle, A.,Yue, W.W.,Froese, D.S.,McCorvie, T.J.
Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase.
Nat Commun, 15:3248-3248, 2024

PubMed Abstract: 5,10-methylenetetrahydrofolate reductase (MTHFR) commits folate-derived one-carbon units to generate the methyl-donor S-adenosyl-L-methionine (SAM). Eukaryotic MTHFR appends to the well-conserved catalytic domain (CD) a unique regulatory domain (RD) that confers feedback inhibition by SAM. Here we determine the cryo-electron microscopy structures of human MTHFR bound to SAM and its demethylated product S-adenosyl-L-homocysteine (SAH). In the active state, with the RD bound to a single SAH, the CD is flexible and exposes its active site for catalysis. However, in the inhibited state the RD pocket is remodelled, exposing a second SAM-binding site that was previously occluded. Dual-SAM bound MTHFR demonstrates a substantially rearranged inter-domain linker that reorients the CD, inserts a loop into the active site, positions Tyr404 to bind the cofactor FAD, and blocks substrate access. Our data therefore explain the long-distance regulatory mechanism of MTHFR inhibition, underpinned by the transition between dual-SAM and single-SAH binding in response to cellular methylation status.

PubMed: 38622112
DOI: 10.1038/s41467-024-47174-y

実験手法

ELECTRON MICROSCOPY (2.8 Å)