Journal Article

FZJ-2019-00780

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes

Schiebel, J. ; Gaspari, R. ; Wulsdorf, T. ; Ngo, K. ; Sohn, C. ; Schrader, T. E.FZJ* ; Cavalli, A. ; Ostermann, A.MLZ* ; Heine, A. (Corresponding author) ; Klebe, G. (Corresponding author)

2018
Nature Publishing Group UK [London]

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Please use a persistent id in citations: http://hdl.handle.net/2128/21480  doi:10.1038/s41467-018-05769-2

Abstract: 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.

Keyword(s): Health and Life (1st) ; Biology (2nd)

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Contributing Institute(s):

1. JCNS-FRM-II (JCNS-FRM-II)
2. Neutronenstreuung (Neutronenstreuung ; JCNS-1)

Research Program(s):

1. 6G15 - FRM II / MLZ (POF3-6G15) (POF3-6G15)
2. 6G4 - Jülich Centre for Neutron Research (JCNS) (POF3-623) (POF3-623)
3. 6215 - Soft Matter, Health and Life Sciences (POF3-621) (POF3-621)

Experiment(s):

1. BIODIFF: Diffractometer for large unit cells (NL1)

Appears in the scientific report 2018

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