ArticleProceedings of the National Academy of Sciences of the United States of America2014
Measurement of histidine pKa values and tautomer populations in invisible protein states.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed.
- When carbonyls beat aromaticity: an additive framework for predicting tautomeric preferences.Chemical science · 2026Article
- Dynamic and Catalytic Multiphase Coacervates.Biomacromolecules · 2026Article
- A histidine switch controls the pH-responsive self-assembly of a helical protein filament.bioRxiv : the preprint server for biology · 2026Article
- Impact of Amino Acid Excipients on icIEF Method Development in Protein Therapeutics: A Formulation-Aware Analytical Framework.AAPS PharmSciTech · 2026Article
- Modulation of Fructose Transfer Process for Promoting Apparent Isomerization Activity of Amylosucrase fromJournal of agricultural and food chemistry · 2026Article
- HomozygousFrontiers in cardiovascular medicine · 2026Article
- Extended Plasmonic Nanostructures Templated by Tobacco Mosaic Virus Coat Protein.Small (Weinheim an der Bergstrasse, Germany) · 2025Article
- A histidine switch regulates pH-dependent filament formation by the caspase-9 CARD.bioRxiv : the preprint server for biology · 2025Article
- Proton Transfer Kinetics in Histidine Side Chains Determined by pH-Dependent Multi-Nuclear NMR Relaxation.Journal of the American Chemical Society · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Probing the role of the protonation state of a minor groove-linker histidine in Exd-Hox-DNA binding.Biophysical journal · 2024Article
- Significance of Histidine Hydrogen-Deuterium Exchange Mass Spectrometry in Protein Structural Biology.Biology · 2024Review
- AlphaFold2 modeling and molecular dynamics simulations of an intrinsically disordered protein.PloS one · 2024Article
- Computational infrared and Raman spectra by hybrid QM/MM techniques: a study on molecular and catalytic material systems.Philosophical transactions. Series A, Mathematical, physical, and engineering sciences · 2023Article
- Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions.Biochemistry · 2023Article
- Slow Protein Dynamics Elicits New Enzymatic Functions by Means of Epistatic Interactions.Molecular biology and evolution · 2022Article
- Principles of target DNA cleavage and the role of Mg2+ in the catalysis of CRISPR-Cas9.Nature catalysis · 2022Article
- Targeting Individual Tautomers in Equilibrium by Resonant Inelastic X-ray Scattering.The journal of physical chemistry letters · 2022Article
- NMR methods for exploring 'dark' states in ligand binding and protein-protein interactions.Progress in nuclear magnetic resonance spectroscopy · 2022Review
- Protonation State of an Important Histidine from High Resolution Structures of Lytic Polysaccharide Monooxygenases.Biomolecules · 2022Article
5 more citing papers are in PubMed but not listed here.
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2 authors.
Funding
Abstract
The histidine imidazole side chain plays a critical role in protein function and stability. Its importance for catalysis is underscored by the fact that histidines are localized to active sites in ∼ 50% of all enzymes. NMR spectroscopy has become an important tool for studies of histidine side chains through the measurement of site-specific pK(a)s and tautomer populations. To date, such studies have been confined to observable protein ground states; however, a complete understanding of the role of histidine electrostatics in protein function and stability requires that similar investigations be extended to rare, transiently formed conformers that populate the energy landscape, yet are often "invisible" in standard NMR spectra. Here we present NMR experiments and a simple strategy for studies of such conformationally excited states based on measurement of histidine (13)Cγ, (13)Cδ2 chemical shifts and (1)Hε-(13)Cε one-bond scalar couplings. The methodology is first validated and then used to obtain pKa values and tautomer distributions for histidine residues of an invisible on-pathway folding intermediate of the colicin E7 immunity protein. Our results imply that the side chains of H40 and H47 are exposed in the intermediate state and undergo significant conformational rearrangements during folding to the native structure. Further, the pKa values explain the pH-dependent stability differences between native and intermediate states over the pH range 5.5-6.5 and they suggest that imidazole deprotonation is not a barrier to the folding of this protein.
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