ArticleJournal of the American Chemical Society2015
Ligand-Induced Proton Transfer and Low-Barrier Hydrogen Bond Revealed by X-ray Crystallography.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 95 citations in OpenAlex.
- Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds.Biochemistry · 2026Article
- QM/MM Free Energy Calculations of IRE1 Reveal a Unique Protonation State of the Catalytic Lys599.Journal of computational chemistry · 2025Article
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds.bioRxiv : the preprint server for biology · 2025Article
- Alpha and Omega Classification of β-Lactamase/Transpeptidase-like Superfamily Proteins Based on the Comparison of Their Structural Catalytic Cores.Molecules (Basel, Switzerland) · 2025Article
- Dynamic interchange between two protonation states is characteristic of active sites of cholinesterases.Protein science : a publication of the Protein Society · 2024Article
- Time-resolved crystallography of boric acid binding to the active site serine of the β-lactamase CTX-M-14 and subsequent 1,2-diol esterification.Communications chemistry · 2024Article
- Drug Discovery in the Field of β-Lactams: An Academic Perspective.Antibiotics (Basel, Switzerland) · 2024Review
- Structure of a ribonucleotide reductase R2 protein radical.Science (New York, N.Y.) · 2023Article
- Correction to "Bifurcated Hydrogen Bonds in a Peptide Crystal Unveiled by X-ray Diffraction and Polarized Raman Spectroscopy".Crystal growth & design · 2023Article
- Biochemical and Structural Characterization of CRH-1, a Carbapenemase from Chromobacterium haemolyticum Related to KPC β-Lactamases.Antimicrobial agents and chemotherapy · 2023Article
- Mapping the determinants of catalysis and substrate specificity of the antibiotic resistance enzyme CTX-M β-lactamase.Communications biology · 2023Article
- Slow Protein Dynamics Elicits New Enzymatic Functions by Means of Epistatic Interactions.Molecular biology and evolution · 2022Article
- True-atomic-resolution insights into the structure and functional role of linear chains and low-barrier hydrogen bonds in proteins.Nature structural & molecular biology · 2022Article
- Structural basis to repurpose boron-based proteasome inhibitors Bortezomib and Ixazomib as β-lactamase inhibitors.Scientific reports · 2022Article
- Effective prediction of short hydrogen bonds in proteins via machine learning method.Scientific reports · 2022Article
- Mutation of the conserved Asp-Asp pair impairs the structure, function, and inhibition of CTX-M Class A β-lactamase.FEBS letters · 2021Article
- Protonation Equilibrium in the Active Site of the Photoactive Yellow Protein.Molecules (Basel, Switzerland) · 2021Article
- Structural and Biochemical Characterization of the Novel CTX-M-151 Extended-Spectrum β-Lactamase and Its Inhibition by Avibactam.Antimicrobial agents and chemotherapy · 2021Article
- Lighting up solid states using a rubber.Nature communications · 2021Article
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
Ligand binding can change the pKa of protein residues and influence enzyme catalysis. Herein, we report three ultrahigh resolution X-ray crystal structures of CTX-M β-lactamase, directly visualizing protonation state changes along the enzymatic pathway: apo protein at 0.79 Å, precovalent complex with nonelectrophilic ligand at 0.89 Å, and acylation transition state (TS) analogue at 0.84 Å. Binding of the noncovalent ligand induces a proton transfer from the catalytic Ser70 to the negatively charged Glu166, and the formation of a low-barrier hydrogen bond (LBHB) between Ser70 and Lys73, with a length of 2.53 Å and the shared hydrogen equidistant from the heteroatoms. QM/MM reaction path calculations determined the proton transfer barrier to be 1.53 kcal/mol. The LBHB is absent in the other two structures although Glu166 remains neutral in the covalent complex. Our data represents the first X-ray crystallographic example of a hydrogen engaged in an enzymatic LBHB, and demonstrates that desolvation of the active site by ligand binding can provide a protein microenvironment conducive to LBHB formation. It also suggests that LBHBs may contribute to stabilization of the TS in general acid/base catalysis together with other preorganized features of enzyme active sites. These structures reconcile previous experimental results suggesting alternatively Glu166 or Lys73 as the general base for acylation, and underline the importance of considering residue protonation state change when modeling protein-ligand interactions. Additionally, the observation of another LBHB (2.47 Å) between two conserved residues, Asp233 and Asp246, suggests that LBHBs may potentially play a special structural role in proteins.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.