8OOG
Crystal structure of human MAT2a with S-Adenosylmethionine and a fragment bound in a novel pocket
Summary for 8OOG
Entry DOI | 10.2210/pdb8oog/pdb |
Descriptor | S-adenosylmethionine synthase isoform type-2, S-ADENOSYLMETHIONINE, 6-oxidanyl-1,3-benzoxathiol-2-one, ... (5 entities in total) |
Functional Keywords | methionine adenosyltransferase, s-adenosylmethionine synthetase, fragment screen, allosteric binder, transferase |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 1 |
Total formula weight | 44658.70 |
Authors | Schimpl, M. (deposition date: 2023-04-05, release date: 2023-07-12, Last modification date: 2024-06-19) |
Primary citation | La Sala, G.,Pfleger, C.,Kack, H.,Wissler, L.,Nevin, P.,Bohm, K.,Janet, J.P.,Schimpl, M.,Stubbs, C.J.,De Vivo, M.,Tyrchan, C.,Hogner, A.,Gohlke, H.,Frolov, A.I. Combining structural and coevolution information to unveil allosteric sites. Chem Sci, 14:7057-7067, 2023 Cited by PubMed Abstract: Understanding allosteric regulation in biomolecules is of great interest to pharmaceutical research and computational methods emerged during the last decades to characterize allosteric coupling. However, the prediction of allosteric sites in a protein structure remains a challenging task. Here, we integrate local binding site information, coevolutionary information, and information on dynamic allostery into a structure-based three-parameter model to identify potentially hidden allosteric sites in ensembles of protein structures with orthosteric ligands. When tested on five allosteric proteins (LFA-1, p38-α, GR, MAT2A, and BCKDK), the model successfully ranked all known allosteric pockets in the top three positions. Finally, we identified a novel druggable site in MAT2A confirmed by X-ray crystallography and SPR and a hitherto unknown druggable allosteric site in BCKDK validated by biochemical and X-ray crystallography analyses. Our model can be applied in drug discovery to identify allosteric pockets. PubMed: 37389247DOI: 10.1039/d2sc06272k PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.384 Å) |
Structure validation
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