TY  - JOUR
AU  - Schiebel, Johannes
AU  - Gaspari, Roberto
AU  - Wulsdorf, Tobias
AU  - Ngo, Khang
AU  - Sohn, Christian
AU  - Schrader, Tobias E.
AU  - Cavalli, Andrea
AU  - Ostermann, Andreas
AU  - Heine, Andreas
AU  - Klebe, Gerhard
TI  - Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes
JO  - Nature Communications
VL  - 9
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - FZJ-2019-00780
SP  - 3559
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30177695
UR  - <Go to ISI:>//WOS:000443465900001
DO  - DOI:10.1038/s41467-018-05769-2
UR  - https://juser.fz-juelich.de/record/859974
ER  -