Structural highlights
Function
METK2_HUMAN Catalyzes the formation of S-adenosylmethionine from methionine and ATP.
Publication Abstract from PubMed
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-alpha, 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.
Combining structural and coevolution information to unveil allosteric sites.,La Sala G, Pfleger C, Kack H, Wissler L, Nevin P, Bohm K, Janet JP, Schimpl M, Stubbs CJ, De Vivo M, Tyrchan C, Hogner A, Gohlke H, Frolov AI Chem Sci. 2023 Jun 8;14(25):7057-7067. doi: 10.1039/d2sc06272k. eCollection 2023 , Jun 28. PMID:37389247[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ La Sala G, Pfleger C, Käck H, Wissler L, Nevin P, Böhm K, Janet JP, Schimpl M, Stubbs CJ, De Vivo M, Tyrchan C, Hogner A, Gohlke H, Frolov AI. Combining structural and coevolution information to unveil allosteric sites. Chem Sci. 2023 Jun 8;14(25):7057-7067. PMID:37389247 doi:10.1039/d2sc06272k
