ArticleJournal of the American Chemical Society2008
Testing geometrical discrimination within an enzyme active site: constrained hydrogen bonding in the ketosteroid isomerase oxyanion hole.
Article in Journal of the American Chemical Society, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed.
- Structural and functional effects of phosphopriming and scaffolding in the kinase GSK-3β.Science signaling · 2024Article
- Proton transfer reactions: From photochemistry to biochemistry and bioenergetics.BBA advances · 2023Article
- High throughput and quantitative enzymology in the genomic era.Current opinion in structural biology · 2021Review
- Heme-binding enables allosteric modulation in an ancient TIM-barrel glycosidase.Nature communications · 2021Article
- The Recognition of Unrelated Ligands by Identical Proteins.ACS chemical biology · 2018Article
- Electric Fields and Fast Protein Dynamics in Enzymes.The journal of physical chemistry letters · 2017Article
- Electric Fields and Enzyme Catalysis.Annual review of biochemistry · 2017Review
- Kemp Eliminase Activity of Ketosteroid Isomerase.Biochemistry · 2017Article
- Handicap-Recover Evolution Leads to a Chemically Versatile, Nucleophile-Permissive Protease.Chembiochem : a European journal of chemical biology · 2015Article
- Modulation of inherent dynamical tendencies of the bisabolyl cationChemical science · 2015Article
- Quantum delocalization of protons in the hydrogen-bond network of an enzyme active site.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Article
- Heterogeneous preferential solvation of water and trifluoroethanol in homologous lysozymes.The journal of physical chemistry. B · 2014Article
- The Hydractinia echinata test-system. III: Structure-toxicity relationship study of some azo-, azo-anilide, and diazonium salt derivatives.Molecules (Basel, Switzerland) · 2014Article
- Using unnatural amino acids to probe the energetics of oxyanion hole hydrogen bonds in the ketosteroid isomerase active site.Journal of the American Chemical Society · 2014Article
- Acceleration of an aromatic Claisen rearrangement via a designed spiroligozyme catalyst that mimics the ketosteroid isomerase catalytic dyad.Journal of the American Chemical Society · 2014Article
- Quantitative dissection of hydrogen bond-mediated proton transfer in the ketosteroid isomerase active site.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Fundamental challenges in mechanistic enzymology: progress toward understanding the rate enhancements of enzymes.Biochemistry · 2013Review
- Why nature really chose phosphate.Quarterly reviews of biophysics · 2013Review
- Psychrophilic enzymes: from folding to function and biotechnology.Scientifica · 2013Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Enzymes are classically proposed to accelerate reactions by binding substrates within active-site environments that are structurally preorganized to optimize binding interactions with reaction transition states rather than ground states. This is a remarkably formidable task considering the limited 0.1-1 A scale of most substrate rearrangements. The flexibility of active-site functional groups along the coordinate of substrate rearrangement, the distance scale on which enzymes can distinguish structural rearrangement, and the energetic significance of discrimination on that scale remain open questions that are fundamental to a basic physical understanding of enzyme active sites and catalysis. We bring together 1.2-1.5 A resolution X-ray crystallography, (1)H and (19)F NMR spectroscopy, quantum mechanical calculations, and transition-state analogue binding measurements to test the distance scale on which noncovalent forces can constrain the structural relaxation or translation of side chains and ligands along a specific coordinate and the energetic consequences of such geometric constraints within the active site of bacterial ketosteroid isomerase (KSI). Our results strongly suggest that packing and binding interactions within the KSI active site can constrain local side-chain reorientation and prevent hydrogen bond shortening by 0.1 A or less. Further, this constraint has substantial energetic effects on ligand binding and stabilization of negative charge within the oxyanion hole. These results provide evidence that subtle geometric effects, indistinguishable in most X-ray crystallographic structures, can have significant energetic consequences and highlight the importance of using synergistic experimental approaches to dissect enzyme function.
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