8QA4
MTHFR + SAH symmetric dis-inhibited state
Summary for 8QA4
| Entry DOI | 10.2210/pdb8qa4/pdb |
| EMDB information | 18298 |
| Descriptor | Methylenetetrahydrofolate reductase (NADPH), S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total) |
| Functional Keywords | dis-inhibited, allosteric, folate, s-adenosylhomocysteine, flavoprotein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 151691.21 |
| Authors | Blomgren, L.K.M.,Yue, W.W.,Froese, D.S.,McCorvie, T.J. (deposition date: 2023-08-22, release date: 2023-11-08, Last modification date: 2024-05-01) |
| Primary citation | 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 Cited by 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: 38622112DOI: 10.1038/s41467-024-47174-y PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
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