5MNA

Cationic trypsin in complex with aniline (deuterated sample at 295 K)

Summary for 5MNA

• Entry DOI: 10.2210/pdb5mna/pdb
• Descriptor: Cationic trypsin, CALCIUM ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hydrogen bonding, protonation, protein-ligand interaction, hydrolase
• Biological source: Bos taurus (Bovine)
• Cellular location: Secreted, extracellular space: P00760
• Total number of polymer chains: 1
• Total formula weight: 23553.55

Authors

Schiebel, J.,Heine, A.,Klebe, G. (deposition date: 2016-12-13, release date: 2017-05-24, Last modification date: 2024-01-17)

Primary citation

Schiebel, J.,Gaspari, R.,Sandner, A.,Ngo, K.,Gerber, H.D.,Cavalli, A.,Ostermann, A.,Heine, A.,Klebe, G.
Charges Shift Protonation: Neutron Diffraction Reveals that Aniline and 2-Aminopyridine Become Protonated Upon Binding to Trypsin.
Angew. Chem. Int. Ed. Engl., 56:4887-4890, 2017

PubMed Abstract: Hydrogen atoms play a key role in protein-ligand recognition. They determine the quality of established H-bonding networks and define the protonation of bound ligands. Structural visualization of H atoms by X-ray crystallography is rarely possible. We used neutron diffraction to determine the positions of the hydrogen atoms in the ligands aniline and 2-aminopyridine bound to the archetypical serine protease trypsin. The resulting structures show the best resolution so far achieved for proteins larger than 100 residues and allow an accurate description of the protonation states and interactions with nearby water molecules. Despite its low pK of 4.6 and a large distance of 3.6 Å to the charged Asp189 at the bottom of the S1 pocket, the amino group of aniline becomes protonated, whereas in 2-aminopyridine, the pyridine nitrogen picks up the proton although its amino group is 1.6 Å closer to Asp189. Therefore, apart from charge-charge distances, tautomer stability is decisive for the resulting binding poses, an aspect that is pivotal for predicting correct binding.

PubMed: 28371253
DOI: 10.1002/anie.201701038

Experimental method

X-RAY DIFFRACTION (1.441 Å)