ArticleJournal of the American Chemical Society2012
Simulations of allosteric motions in the zinc sensor CzrA.
Article in Journal of the American Chemical Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- A Zur-dependent regulatory RNA involved in maintaining zinc homeostasis in Staphylococcus aureus.Nucleic acids research · 2026Article
- BR-Bodies Facilitate Adaptive Responses and Survival During Copper Stress inbioRxiv : the preprint server for biology · 2025Article
- AsJournal of the American Chemical Society · 2024Article
- Article
- Combined Theoretical, Bioinformatic, and Biochemical Analyses of RNA Editing by Adenine Base Editors.The CRISPR journal · 2022Article
- A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors.Proteins · 2022Article
- Parametrization of Trivalent and Tetravalent Metal Ions for the OPC3, OPC, TIP3P-FB, and TIP4P-FB Water Models.Journal of chemical theory and computation · 2021Article
- Dynamic Characterization of the Human Heme Nitric Oxide/Oxygen (HNOX) Domain under the Influence of Diatomic Gaseous Ligands.International journal of molecular sciences · 2019Article
- Functional Role of Solvent Entropy and Conformational Entropy of Metal Binding in a Dynamically Driven Allosteric System.Journal of the American Chemical Society · 2018Article
- Entropy redistribution controls allostery in a metalloregulatory protein.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Metal Ion Modeling Using Classical Mechanics.Chemical reviews · 2017Review
- Solution NMR Spectroscopy for the Study of Enzyme Allostery.Chemical reviews · 2016Review
- DFTB3 Parametrization for Copper: The Importance of Orbital Angular Momentum Dependence of Hubbard Parameters.Journal of chemical theory and computation · 2015Article
- Role of substrate dynamics in protein prenylation reactions.Accounts of chemical research · 2015Review
- Parametrization of DFTB3/3OB for magnesium and zinc for chemical and biological applications.The journal of physical chemistry. B · 2015Article
- Parameterization of highly charged metal ions using the 12-6-4 LJ-type nonbonded model in explicit water.The journal of physical chemistry. B · 2015Article
- Characterizing solution surface loop conformational flexibility of the GM2 activator protein.The journal of physical chemistry. B · 2014Article
- Structure and dynamics of the N-terminal domain of the Cu(I) binding protein CusB.Biochemistry · 2013Article
- Stabilization of different types of transition states in a single enzyme active site: QM/MM analysis of enzymes in the alkaline phosphatase superfamily.Journal of the American Chemical Society · 2013Article
- Rational Design of Particle Mesh Ewald Compatible Lennard-Jones Parameters for +2 Metal Cations in Explicit Solvent.Journal of chemical theory and computation · 2013Article
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5 authors.
Funding
Abstract
The zinc sensing transcriptional repressor Staphylococcus aureus CzrA represents an excellent model system to understand how metal sensor proteins maintain cellular metal homeostasis. Zn(II) binding induces a quaternary structural switch from a "closed" conformation to a more "open" conformation, reducing the DNA binding affinity by 4 orders of magnitude. In this study, we use classical molecular dynamics and quantum mechanical/molecular mechanical molecular dynamics simulations to investigate the molecular basis for the large conformational motions and allosteric coupling free energy (~6 kcal/mol) associated with Zn(II) binding. Our simulations successfully capture the closed to open allosteric switching in DNA bound CzrA on Zn(II) binding. They reveal that zinc binding quenches global conformational sampling by CzrA, whereas DNA binding enhances the mobility of residues in the allosteric metal binding sites. These findings are in close agreement with experiments. We also identify networks of residues involved in correlated and anticorrelated motions that connect the metal binding and DNA binding sites. Our analysis of the essential dynamics shows metal ion binding to be the primary driving force for the quaternary structural change in CzrA. We also show that Zn(II) binding limits the conformational space sampled by CzrA and causes the electrostatic surface potential at the DNA binding interface to become less favorable toward DNA binding. Finally, our simulations provide strong support for a proposed hydrogen-bonding pathway that physically connects the metal binding residue, His97, to the DNA binding interface through the αR helix that is present only in the Zn(II)-bound state. Overall, our simulations provide molecular-level insights into the mechanism of allosteric regulation by CzrA and demonstrate the importance of protein motion in its biological activity.
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