%0 Journal Article
%A Schiebel, Johannes
%A Gaspari, Roberto
%A Wulsdorf, Tobias
%A Ngo, Khang
%A Sohn, Christian
%A Schrader, Tobias E.
%A Cavalli, Andrea
%A Ostermann, Andreas
%A Heine, Andreas
%A Klebe, Gerhard
%T Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes
%J Nature Communications
%V 9
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M FZJ-2019-00780
%P 3559
%D 2018
%X Hydrogen 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:30177695
%U <Go to ISI:>//WOS:000443465900001
%R 10.1038/s41467-018-05769-2
%U https://juser.fz-juelich.de/record/859974