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000859974 1001_ $$0P:(DE-HGF)0$$aSchiebel, Johannes$$b0
000859974 245__ $$aIntriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes
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000859974 520__ $$aHydrogen bonds are key interactions determining protein-ligand binding affinity and therefore fundamental to any biological process. Unfortunately, explicit structural information about hydrogen positions and thus H-bonds in protein-ligand complexes is extremely rare and similarly the important role of water during binding remains poorly understood. Here, we report on neutron structures of trypsin determined at very high resolutions ≤1.5 Å in uncomplexed and inhibited state complemented by X-ray and thermodynamic data and computer simulations. Our structures show the precise geometry of H-bonds between protein and the inhibitors N-amidinopiperidine and benzamidine along with the dynamics of the residual solvation pattern. Prior to binding, the ligand-free binding pocket is occupied by water molecules characterized by a paucity of H-bonds and high mobility resulting in an imperfect hydration of the critical residue Asp189. This phenomenon likely constitutes a key factor fueling ligand binding via water displacement and helps improving our current view on water influencing protein–ligand recognition.
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000859974 7001_ $$0P:(DE-HGF)0$$aGaspari, Roberto$$b1
000859974 7001_ $$0P:(DE-HGF)0$$aWulsdorf, Tobias$$b2
000859974 7001_ $$0P:(DE-HGF)0$$aNgo, Khang$$b3
000859974 7001_ $$0P:(DE-HGF)0$$aSohn, Christian$$b4
000859974 7001_ $$0P:(DE-Juel1)138266$$aSchrader, Tobias E.$$b5
000859974 7001_ $$0P:(DE-HGF)0$$aCavalli, Andrea$$b6
000859974 7001_ $$00000-0002-1477-5590$$aOstermann, Andreas$$b7
000859974 7001_ $$0P:(DE-HGF)0$$aHeine, Andreas$$b8$$eCorresponding author
000859974 7001_ $$0P:(DE-HGF)0$$aKlebe, Gerhard$$b9$$eCorresponding author
000859974 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-018-05769-2$$gVol. 9, no. 1, p. 3559$$n1$$p3559$$tNature Communications$$v9$$x2041-1723$$y2018
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