7L1A
Human Methionine Adenosyltransferase 2A bound to Methylthioadenosine and inhibitor, di-imido triphosphate (PNPNP)
Summary for 7L1A
| Entry DOI | 10.2210/pdb7l1a/pdb |
| Descriptor | S-adenosylmethionine synthase isoform type-2, MAGNESIUM ION, POTASSIUM ION, ... (8 entities in total) |
| Functional Keywords | s-adenosylmethionine, sam synthetase, enzyme mechanism, inhibitor, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 47149.43 |
| Authors | Niland, C.N.,Fedorov, E.,Schramm, V.L.,Ghosh, A. (deposition date: 2020-12-14, release date: 2021-03-17, Last modification date: 2023-10-18) |
| Primary citation | Niland, C.N.,Ghosh, A.,Cahill, S.M.,Schramm, V.L. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A. Biochemistry, 60:791-801, 2021 Cited by PubMed Abstract: -Adenosyl-l-methionine (AdoMet) is synthesized by the MAT2A isozyme of methionine adenosyltransferase in most human tissues and in cancers. Its contribution to epigenetic control has made it a target for anticancer intervention. A recent kinetic isotope effect analysis of MAT2A demonstrated a loose nucleophilic transition state. Here we show that MAT2A has a sequential mechanism with a rate-limiting step of formation of AdoMet, followed by rapid hydrolysis of the β-γ bond of triphosphate, and rapid release of phosphate and pyrophosphate. MAT2A catalyzes the slow hydrolysis of both ATP and triphosphate in the absence of other reactants. Positional isotope exchange occurs with O as the 5'-oxygen of ATP. Loss of the triphosphate is sufficiently reversible to permit rotation and recombination of the α-phosphoryl group of ATP. Adenosine (α-β or β-γ)-imido triphosphates are slow substrates, and the respective imido triphosphates are inhibitors. The hydrolytically stable (α-β, β-γ)-diimido triphosphate (PNPNP) is a nanomolar inhibitor. The MAT2A protein structure is highly stabilized against denaturation by binding of PNPNP. A crystal structure of MAT2A with 5'-methylthioadenosine and PNPNP shows the ligands arranged appropriately in the ATP binding site. Two magnesium ions chelate the α- and γ-phosphoryl groups of PNPNP. The β-phosphoryl oxygen is in contact with an essential potassium ion. Imidophosphate derivatives provide contact models for the design of catalytic site ligands for MAT2A. PubMed: 33656855DOI: 10.1021/acs.biochem.0c00998 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.25 Å) |
Structure validation
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