6sw5

Crystal structure of the human S-adenosylmethionine synthetase 1 (ligand-free form)Crystal structure of the human S-adenosylmethionine synthetase 1 (ligand-free form)

Structural highlights 6sw5 is a 4 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 2.35Å Ligands: , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease METK1_HUMAN Defects in MAT1A are the cause of methionine adenosyltransferase deficiency (MATD) [MIM:250850; also called MAT I/III deficiency. MATD is an inborn error of metabolism resulting in isolated hypermethioninemia. Most patients have no clinical abnormalities, although some neurologic symptoms may be present in rare cases with severe loss of methionine adenosyltransferase activity. Function METK1_HUMAN Catalyzes the formation of S-adenosylmethionine from methionine and ATP. Publication Abstract from PubMed Methionine adenosyltransferase (MAT) deficiency, characterized by isolated persistent hypermethioninemia (IPH), is caused by mutations in the MAT1A gene encoding MATalphal, one of the major hepatic enzymes. Most of the associated hypermethioninemic conditions are inherited as autosomal recessive traits; however, dominant inheritance of hypermethioninemia is caused by an Arg264His (R264H) mutation. This mutation has been confirmed in a screening programme of newborns as the most common mutation in babies with IPH. Arg264 makes an inter-subunit salt bridge located at the dimer interface where the active site assembles. Here, it is demonstrated that the R264H mutation results in greatly reduced MAT activity, while retaining its ability to dimerize, indicating that the lower activity arises from alteration at the active site. The first crystallographic structure of the apo form of the wild-type MATalphal enzyme is provided, which shows a tetrameric assembly in which two compact dimers combine to form a catalytic tetramer. In contrast, the crystal structure of the MATalphal R264H mutant reveals a weaker dimeric assembly, suggesting that the mutation lowers the affinity for dimer-dimer interaction. The formation of a hetero-oligomer with the regulatory MATbetaV1 subunit or incubation with a quinolone-based compound (SCR0911) results in the near-full recovery of the enzymatic activity of the pathogenic mutation R264H, opening a clear avenue for a therapeutic solution based on chemical interventions that help to correct the defect of the enzyme in its ability to metabolize methionine. Structural basis of the dominant inheritance of hypermethioninemia associated with the Arg264His mutation in the MAT1A gene.,Panmanee J, Antonyuk SV, Hasnain SS Acta Crystallogr D Struct Biol. 2020 Jun 1;76(Pt 6):594-607. doi:, 10.1107/S2059798320006002. Epub 2020 May 29. PMID:32496220 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also S-adenosylmethionine synthetase 3D structures

spinqualitylabelsall models 6sw5, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image