ArticleBiochemistry2013
P450cin active site water: implications for substrate binding and solvent accessibility.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Structural insights into choline-O-sulfatase reveal the molecular determinants for ligand binding.Acta crystallographica. Section D, Structural biology · 2022Article
- An Engineered Glutamate in Biosynthetic Models of Heme-Copper Oxidases Drives Complete Product Selectivity by Tuning the Hydrogen-Bonding Network.Biochemistry · 2021Article
- Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors.Scientific reports · 2018Article
- Conformational Mobility in Cytochrome P450 3A4 Explored by Pressure-Perturbation EPR Spectroscopy.Biophysical journal · 2016Article
- Elucidating nitric oxide synthase domain interactions by molecular dynamics.Protein science : a publication of the Protein Society · 2016Article
- Structure-based design of bacterial nitric oxide synthase inhibitors.Journal of medicinal chemistry · 2015Article
- Anatomy of enzyme channels.BMC bioinformatics · 2014Article
- Cholesterol ester oxidation by mycobacterial cytochrome P450.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
In P450cin, Tyr81, Asp241, Asn242, two water molecules, and the substrate participate in a complex H-bonded network. The role of this H-bonded network in substrate binding and catalysis has been probed by crystallography, spectroscopy, kinetics, isothermal titration calorimetry (ITC), and molecular dynamics. For the Y81F mutant, the substrate binds about 20-fold more weakly and Vmax decreases by about 30% in comparison to WT. The enhanced susceptibility of the heme to H₂O₂-mediated destruction in Y81F suggests that this mutant favors the open, low-spin conformational state. Asn242 H-bonds directly with the substrate, and replacing this residue with Ala results in water taking the place of the missing Asn side chain. This mutant exhibits a 70% decrease in activity. Crystal structures and molecular dynamics simulations of substrate-bound complexes show that the solvent has more ready access to the active site, especially for the N242A mutant. This accounts for about a 64% uncoupling of electron transfer from substrate hydroxylation. These data indicate the importance of the interconnected water network on substrate binding and on the open/closed conformational equilibrium, which are both critically important for maintaining high-coupling efficiency.
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Registered trials
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.