ArticleProceedings of the National Academy of Sciences of the United States of America2017
Structural basis for ligand binding to an enzyme by a conformational selection pathway.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 75 citations in OpenAlex.
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- A Foundational Shift in Models for Enzyme Function.Journal of the American Chemical Society · 2025Review
- Toward the Prediction of Binding Events in Very Flexible, Allosteric, Multidomain Proteins.Journal of chemical information and modeling · 2025Article
- Optimizing Ligand Valency to Maximize Tendon Accumulation of Peptide-Targeted Nanoparticles.ACS applied materials & interfaces · 2024Article
- Predicting binding events in very flexible, allosteric, multi-domain proteins.bioRxiv : the preprint server for biology · 2024Article
- Repurposing of known drugs from multiple libraries to identify novel and potential selective inhibitors of HDAC6 viaHeliyon · 2024Article
- Magnesium induced structural reorganization in the active site of adenylate kinase.Science advances · 2024Article
- CryoEM-sampling of metastable conformations appearing in cofactor-ligand association and catalysis of glutamate dehydrogenase.Scientific reports · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Elucidating Dynamics of Adenylate Kinase from Enzyme Opening to Ligand Release.Journal of chemical information and modeling · 2024Article
- Insights into Enzymatic Catalysis from Binding and Hydrolysis of Diadenosine Tetraphosphate byBiochemistry · 2023Article
- Allosteric communication between ligand binding domains modulates substrate inhibition in adenylate kinase.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Mechanistic Basis for a Connection between the Catalytic Step and Slow Opening Dynamics of Adenylate Kinase.Journal of chemical information and modeling · 2023Article
- Conformational exchange divergence along the evolutionary pathway of eosinophil-associated ribonucleases.Structure (London, England : 1993) · 2023Article
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteins can bind target molecules through either induced fit or conformational selection pathways. In the conformational selection model, a protein samples a scarcely populated high-energy state that resembles a target-bound conformation. In enzymatic catalysis, such high-energy states have been identified as crucial entities for activity and the dynamic interconversion between ground states and high-energy states can constitute the rate-limiting step for catalytic turnover. The transient nature of these states has precluded direct observation of their properties. Here, we present a molecular description of a high-energy enzyme state in a conformational selection pathway by an experimental strategy centered on NMR spectroscopy, protein engineering, and X-ray crystallography. Through the introduction of a disulfide bond, we succeeded in arresting the enzyme adenylate kinase in a closed high-energy conformation that is on-pathway for catalysis. A 1.9-Å X-ray structure of the arrested enzyme in complex with a transition state analog shows that catalytic sidechains are properly aligned for catalysis. We discovered that the structural sampling of the substrate free enzyme corresponds to the complete amplitude that is associated with formation of the closed and catalytically active state. In addition, we found that the trapped high-energy state displayed improved ligand binding affinity, compared with the wild-type enzyme, demonstrating that substrate binding to the high-energy state is not occluded by steric hindrance. Finally, we show that quenching of fast time scale motions observed upon ligand binding to adenylate kinase is dominated by enzyme-substrate interactions and not by intramolecular interactions resulting from the conformational change.
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