ArticleBiochemistry2017
High-Level Production and Properties of the Cysteine-Depleted Cytochrome P450 3A4.
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
30 citing papers in PubMed, 53 citations in OpenAlex.
- Structural Plasticity and Ligand Promiscuity of CYP3A4 Revealed by Cryo-EM.bioRxiv : the preprint server for biology · 2026Article
- Effects of Newer Veterinary Macrolide Antimicrobials on the CYP3A-Dependent Metabolism in Cattle Liver Microsomes: Potential Metabolic Drug-Drug Interaction with Monensin.Animals : an open access journal from MDPI · 2026Article
- Interaction of cytochrome P450 3A4 with the hydrophilic ligand tetraethylene glycol.Biochemical and biophysical research communications · 2026Article
- Hole migration in cytochrome P450.QRB discovery · 2026Article
- Evaluation of Larger Side-Group Functionalities and the Side/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4.Chemical biology & drug design · 2025Article
- Multi-target Mechanisms of Si-Ni-San on Anxious Insomnia: An Example of Network-pharmacology and Molecular Docking Analysis.Current medicinal chemistry · 2025Article
- A Computational Pipeline Observes the Flexibility and Dynamics of Plant Cytochrome P450 Binding Sites.International journal of molecular sciences · 2024Article
- Interaction of CYP3A4 with the inhibitor cobicistat: Structural and mechanistic insights and comparison with ritonavir.Archives of biochemistry and biophysics · 2024Article
- The Impact of Inorganic Systems and Photoactive Metal Compounds on Cytochrome P450 Enzymes and Metabolism: From Induction to Inhibition.Biomolecules · 2024Review
- Nanodisc-embedded cytochrome P450 P3A4 binds diverse ligands by distributing conformational dynamics to its flexible elements.Journal of inorganic biochemistry · 2023Article
- Investigating a new C2-symmetric testosterone dimer and its dihydrotestosterone analog: Synthesis, antiproliferative activity on prostate cancer cell lines and interaction with CYP3A4.European journal of medicinal chemistry · 2023Article
- Crystal Structure of CYP3A4 Complexed with Fluorol Identifies the Substrate Access Channel as a High-Affinity Ligand Binding Site.International journal of molecular sciences · 2022Article
- Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.International journal of molecular sciences · 2022Article
- Innovative CEuropean journal of medicinal chemistry · 2021Article
- Photosensitive Ru(II) Complexes as Inhibitors of the Major Human Drug Metabolizing Enzyme CYP3A4.Journal of the American Chemical Society · 2021Article
- Homotropic Cooperativity of Midazolam Metabolism by Cytochrome P450 3A4: Insight from Computational Studies.Journal of chemical information and modeling · 2021Article
- Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength.International journal of molecular sciences · 2021Article
- Mechanistic Insights into the Regio- and Stereoselectivities of Testosterone and Dihydrotestosterone Hydroxylation Catalyzed by CYP3A4 and CYP19A1.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.Bioorganic & medicinal chemistry · 2020Article
- Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism.Liver research (Beijing, China) · 2019Article
Corrections and comments
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Authors and funding
1 author at 1 institution in 1 country.
Funding
Abstract
Human drug-metabolizing cytochrome P450 3A4 (CYP3A4) is a dynamic enzyme with a large and highly malleable active site that can fit structurally diverse compounds. Despite extensive investigations, structure-function relationships and conformational dynamics in CYP3A4 are not fully understood. This study was undertaken to engineer a well-expressed and functionally active cysteine-depleted CYP3A4 that can be used in biochemical and biophysical studies. cDNA codon optimization and screening mutagenesis were utilized to boost the level of bacterial expression of CYP3A4 and identify the least harmful substitutions for all six non-heme-ligating cysteines. The C58A/C64M/C98A/C239T/C377A/C468S (Cys-less) mutant was found to be expressed as highly as the optimized wild-type (opt-WT) CYP3A4. The high-resolution X-ray structures of opt-WT and Cys-less CYP3A4 revealed that gene optimization leads to a different folding in the Phe108 and Phe189 regions and promotes binding of the active site glycerol that interlocks Ser119 and Arg212, critical for ligand association, and the hydrophobic cluster adjacent to Phe108. Crowding and decreased flexibility of the active site, as well as structural alterations observed at the C64M, C239T, and C468S mutational sites, might be responsible for the distinct ligand binding behavior of opt-WT and Cys-less CYP3A4. Nonetheless, the Cys-less mutant could be used for structure-function investigations because it orients bromoergocryptine and ritonavir (a high-affinity substrate and a high-potency inhibitor, respectively) like the WT and has a higher activity toward 7-benzyloxy(4-trifluoromethyl)coumarin.
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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.