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Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes
- Source :
- Nature Communications, Vol 9, Iss 1, Pp 1-15 (2018), Nature Communications 9(1), 3559 (2018). doi:10.1038/s41467-018-05769-2, Nature Communications
- Publication Year :
- 2018
- Publisher :
- Nature Portfolio, 2018.
-
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 Šin 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.<br />Trypsin is a serine protease. Here the authors present the high resolution X-ray and neutron diffraction structures of uncomplexed and inhibitor bound trypsin that provide insights into the geometry of H-bonds in the active site of the enzyme and molecular dynamics simulations reveal the kinetics of ligand binding induced desolvation.
- Subjects :
- 0301 basic medicine
Serine Proteinase Inhibitors
Science
General Physics and Astronomy
Ligand
Ligands
Crystallography, X-Ray
General Biochemistry, Genetics and Molecular Biology
Benzamidine
Article
03 medical and health sciences
chemistry.chemical_compound
Residue (chemistry)
Physics and Astronomy (all)
Thermodynamic
Hydrolase
medicine
Molecule
Computer Simulation
Trypsin
lcsh:Science
Multidisciplinary
Crystallography
Biochemistry, Genetics and Molecular Biology (all)
Hydrogen bond
Chemistry (all)
Solvation
Water
Hydrogen Bonding
General Chemistry
Benzamidines
Neutron Diffraction
030104 developmental biology
chemistry
Thermodynamics
lcsh:Q
ddc:500
Serine Proteinase Inhibitor
Protein ligand
medicine.drug
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....c7647127741e4f702e7d10fa191b6eed