5MOQ

Joint X-ray/neutron structure of cationic trypsin in complex with benzamidine

Summary for 5MOQ

• Entry DOI: 10.2210/pdb5moq/pdb
• Related: 5MNH 5MO0
• Descriptor: Cationic trypsin, CALCIUM ION, BENZAMIDINE, ... (5 entities in total)
• Functional Keywords: hydrogen bonding, protonation, protein-ligand interaction, hydrolase
• Biological source: Bos taurus (Bovine)
• Total number of polymer chains: 1
• Total formula weight: 23580.58

Authors

Schiebel, J.,Schrader, T.E.,Ostermann, A.,Heine, A.,Klebe, G. (deposition date: 2016-12-14, release date: 2018-02-28, Last modification date: 2024-11-20)

Primary citation

Schiebel, J.,Gaspari, R.,Wulsdorf, T.,Ngo, K.,Sohn, C.,Schrader, T.E.,Cavalli, A.,Ostermann, A.,Heine, A.,Klebe, G.
Intriguing role of water in protein-ligand binding studied by neutron crystallography on trypsin complexes.
Nat Commun, 9:3559-3559, 2018

PubMed 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.

PubMed: 30177695
DOI: 10.1038/s41467-018-05769-2

Experimental method

NEUTRON DIFFRACTION (1.502 Å)
X-RAY DIFFRACTION (0.93 Å)