8UY2
Methylenetetrahydrofolate reductase from Chaetomium thermophilum DSM 1495, AdoMet-bound, Inhibited (T) State
Summary for 8UY2
| Entry DOI | 10.2210/pdb8uy2/pdb |
| Descriptor | Methylenetetrahydrofolate reductase-like protein, FLAVIN-ADENINE DINUCLEOTIDE, S-ADENOSYLMETHIONINE, ... (8 entities in total) |
| Functional Keywords | 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 |
| Biological source | Thermochaetoides thermophila DSM 1495 |
| Total number of polymer chains | 4 |
| Total formula weight | 288663.74 |
| Authors | Yamada, K.,Mendoza, J.,Koutmos, M. (deposition date: 2023-11-12, release date: 2024-06-19, Last modification date: 2024-07-03) |
| Primary citation | 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 Cited by 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: 38886362DOI: 10.1038/s41467-024-49327-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.83 Å) |
Structure validation
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