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001008583 1001_ $$00000-0001-6565-197X$$aLa Sala, Giuseppina$$b0$$eCorresponding author
001008583 245__ $$aCombining structural and coevolution information to unveil allosteric sites
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001008583 520__ $$aUnderstanding 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.
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001008583 7001_ $$0P:(DE-HGF)0$$aPfleger, Christopher$$b1
001008583 7001_ $$0P:(DE-HGF)0$$aKäck, Helena$$b2
001008583 7001_ $$0P:(DE-HGF)0$$aWissler, Lisa$$b3
001008583 7001_ $$0P:(DE-HGF)0$$aNevin, Philip$$b4
001008583 7001_ $$0P:(DE-HGF)0$$aBöhm, Kerstin$$b5
001008583 7001_ $$0P:(DE-HGF)0$$aJanet, Jon Paul$$b6
001008583 7001_ $$0P:(DE-HGF)0$$aSchimpl, Marianne$$b7
001008583 7001_ $$0P:(DE-HGF)0$$aStubbs, Christopher J.$$b8
001008583 7001_ $$0P:(DE-Juel1)167585$$aDe Vivo, Marco$$b9
001008583 7001_ $$0P:(DE-HGF)0$$aTyrchan, Christian$$b10
001008583 7001_ $$0P:(DE-HGF)0$$aHogner, Anders$$b11
001008583 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b12$$eCorresponding author
001008583 7001_ $$00000-0001-9801-3253$$aFrolov, Andrey I.$$b13$$eCorresponding author
001008583 773__ $$0PERI:(DE-600)2559110-1$$a10.1039/D2SC06272K$$gp. 10.1039.D2SC06272K$$n25$$p7057-7067 $$tChemical science$$v14$$x2041-6520$$y2023
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