9YCU

Protiated human DJ-1, 100K

Summary for 9YCU

• Entry DOI: 10.2210/pdb9ycu/pdb
• Descriptor: Protein deglycase DJ-1, 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: park7, glyoxalase, cyclic phosphoglycerate anhydride hydrolase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 20509.67

Authors

Lin, J.,Kovalevsky, A.,Walker, A.R.,Wilson, M.A. (deposition date: 2025-09-19, release date: 2025-10-08, Last modification date: 2025-12-10)

Primary citation

Lin, J.,Gerlits, O.,Kneller, D.W.,Weiss, K.L.,Coates, L.,Hix, M.A.,Effah, S.Y.,Kovalevsky, A.,Walker, A.R.,Wilson, M.A.
Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds.
Biorxiv, 2025

PubMed Abstract: Hydrogen bonds (H-bonds) are central to biomolecular structure and dynamics. Although H-bonds are typically characterized by well-defined proton positions, proton delocalization can play a key role in facilitating enzyme catalysis and allostery in some systems. Experimentally locating protons is difficult, hampering the study of the proton mobility in H-bonds. We used neutron crystallography and large quantum mechanics/molecular mechanics-Born Oppenheimer molecular dynamics (QM/MM-BOMD) simulations of human DJ-1 and its bacterial homolog YajL to validate atomic resolution X-ray crystallographic bond length analysis, directly visualizing the shared deuteron in a low-barrier hydrogen bond (LBHB) between Glu14-Asp23 in YajL that is a conventional H-bond in DJ-1. In addition, X-ray bond length analysis of protiated and perdeuterated DJ-1 and YajL shows no significant effect of deuteron substitution on these carboxylic acid-carboxylate H-bonds but does reveal an effect at the active site glutamic acid. Residues in the vicinity of Glu14-Asp23 that might favor LBHB formation in YajL were interrogated by mutagenesis of homologous residues in DJ-1. X-ray bond length analysis and QM/MM-BOMD simulations demonstrate that a distal I21T DJ-1 substitution increases proton delocalization in the Glu-Asp H-bond. In addition, simulations show that the extent of proton mobility in the H-bond influences correlated dimer-spanning motions in YajL and DJ-1. In total, we show that mutations within extended H-bonding networks can modulate proton transfer barriers in carboxylic acid-carboxylate H-bonds, allowing proton delocalization to be engineered using combined bioinformatic, structural, and computational information.

PubMed: 41279124
DOI: 10.1101/2025.11.05.686872

Experimental method

X-RAY DIFFRACTION (1.05 Å)