7l1a

Human Methionine Adenosyltransferase 2A bound to Methylthioadenosine and inhibitor, di-imido triphosphate (PNPNP)

spinqualitylabelsall models 7l1a, resolution 1.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7l1a is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.25Å Ligands: ALA, K, MG, MTA, NA, XE1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function METK2_HUMAN Catalyzes the formation of S-adenosylmethionine from methionine and ATP. Publication Abstract from PubMed S-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 beta-gamma 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 (18)O as the 5'-oxygen of ATP. Loss of the triphosphate is sufficiently reversible to permit rotation and recombination of the alpha-phosphoryl group of ATP. Adenosine (alpha-beta or beta-gamma)-imido triphosphates are slow substrates, and the respective imido triphosphates are inhibitors. The hydrolytically stable (alpha-beta, beta-gamma)-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 alpha- and gamma-phosphoryl groups of PNPNP. The beta-phosphoryl oxygen is in contact with an essential potassium ion. Imidophosphate derivatives provide contact models for the design of catalytic site ligands for MAT2A. Mechanism and Inhibition of Human Methionine Adenosyltransferase 2A.,Niland CN, Ghosh A, Cahill SM, Schramm VL Biochemistry. 2021 Mar 16;60(10):791-801. doi: 10.1021/acs.biochem.0c00998. Epub , 2021 Mar 3. PMID:33656855 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also S-adenosylmethionine synthetase 3D structures

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