ArticleBiophysical journal2016
Conformational Mobility in Cytochrome P450 3A4 Explored by Pressure-Perturbation EPR Spectroscopy.
Article in Biophysical journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- A dynamic duo: Copper metalloregulators and continuous-wave electron spin resonance spectroscopy.Biophysical reports · 2026Review
- The role of CYP3A-CYP2E1 interactions in activation of CYP3A enzymes by chronic alcohol exposure.bioRxiv : the preprint server for biology · 2026Article
- A New Fluorogenic Substrate for CYP1A2 and Its Application in Studying the Effects of Alcohol Exposure on Liver Drug Metabolism.bioRxiv : the preprint server for biology · 2026Article
- A new naphthalene-based fluorogenic substrate for cytochrome P450 4A11.The Biochemical journal · 2025Article
- Green synthesis of building blocks, drug candidates and fine chemicals by barochemistry: application of high pressure in organic synthesis.Green chemistry : an international journal and green chemistry resource : GC · 2025Review
- Extended Sampling of Macromolecular Conformations from Uniformly Distributed Points on Multidimensional Normal Mode Hyperspheres.Journal of chemical theory and computation · 2024Article
- NiScientific reports · 2023Article
- Nanodisc-embedded cytochrome P450 P3A4 binds diverse ligands by distributing conformational dynamics to its flexible elements.Journal of inorganic biochemistry · 2023Article
- Allostery-driven changes in dynamics regulate the activation of bacterial copper transcription factor.Protein science : a publication of the Protein Society · 2022Article
- High-Pressure ESR Spectroscopy: On the Rotational Motion of Spin Probes in Pressurized Ionic Liquids.The journal of physical chemistry. B · 2022Article
- Probing functional interactions between cytochromes P450 with principal component analysis of substrate saturation profiles and targeted proteomics.Archives of biochemistry and biophysics · 2021Article
- Effects of alcohol-induced increase in CYP2E1 content in human liver microsomes on the activity and cooperativity of CYP3A4.Archives of biochemistry and biophysics · 2021Article
- Nonadditivity in human microsomal drug metabolism revealed in a study with coumarin 152, a polyspecific cytochrome P450 substrate.Xenobiotica; the fate of foreign compounds in biological systems · 2020Article
- Pressure tolerance of deep-sea enzymes can be evolved through increasing volume changes in protein transitions: a study with lactate dehydrogenases from abyssal and hadal fishes.The FEBS journal · 2020Article
- Structure and Function of the Cytochrome P450 Monooxygenase Cinnamate 4-hydroxylase fromPlant physiology · 2020Article
- Structural and dynamic origins of ESR lineshapes in spin-labeled GB1 domain: the insights from spin dynamics simulations based on long MD trajectories.Scientific reports · 2020Article
- Neonatal cytochrome P450 CYP3A7: A comprehensive review of its role in development, disease, and xenobiotic metabolism.Archives of biochemistry and biophysics · 2019Review
- Steroid bioconjugation to a CYP3A4 allosteric site and its effect on substrate binding and coupling efficiency.Archives of biochemistry and biophysics · 2018Article
- Effects of polymorphic variation on the thermostability of heterogenous populations of CYP3A4 and CYP2C9 enzymes in solution.Scientific reports · 2018Article
- High-pressure EPR spectroscopy studies of theApplied magnetic resonance · 2017Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
We used high hydrostatic pressure as a tool for exploring the conformational landscape of human cytochrome P450 3A4 (CYP3A4) by electron paramagnetic resonance and fluorescence spectroscopy. Site-directed incorporation of a luminescence resonance energy transfer donor-acceptor pair allowed us to identify a pressure-dependent equilibrium between two states of the enzyme, where an increase in pressure increased the spatial separation between the two distantly located fluorophores. This transition is characterized by volume change (ΔV°) and P1/2 values of -36.8 ± 5.0 mL/mol and 1.45 ± 0.33 kbar, respectively, which corresponds to a Keq° of 0.13 ± 0.06, so that only 15% of the enzyme adopts the pressure-promoted conformation at ambient pressure. This pressure-promoted displacement of the equilibrium is eliminated by the addition of testosterone, an allosteric activator. Using site-directed spin labeling, we demonstrated that the pressure- and testosterone-sensitive transition is also revealed by pressure-induced changes in the electron paramagnetic resonance spectra of a nitroxide side chain placed at position 85 or 409 of the enzyme. Furthermore, we observed a pressure-induced displacement of the emission maxima of a solvatochromic fluorophore (7-diethylamino-3-((((2-maleimidyl)ethyl)amino)carbonyl) coumarin) placed at the same positions, which suggests a relocation to a more polar environment. Taken together, the results reveal an effector-dependent conformational equilibrium between open and closed states of CYP3A4 that involves a pronounced change at the interface between the region of α-helices A/A' and the meander loop of the enzyme, where residues 85 and 409 are located. Our study demonstrates the high potential of pressure-perturbation strategies for studying protein conformational landscapes.
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