ArticleBiochemistry2015
Drug modulation of water-heme interactions in low-spin P450 complexes of CYP2C9d and CYP125A1.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Heme Spin Distribution in the Substrate-Free and Inhibited Novel CYP116B5hd: A Multifrequency Hyperfine Sublevel Correlation (HYSCORE) Study.Molecules (Basel, Switzerland) · 2024Article
- Synthesis,Future medicinal chemistry · 2024Article
- Mechanisms of allosteric and mixed mode aromatase inhibitors.RSC chemical biology · 2021Article
- Conformational selection is present in ligand binding to cytochrome P450 19A1 lipoprotein nanodiscs.Journal of inorganic biochemistry · 2020Article
- Multiple drug binding modes in Mycobacterium tuberculosis CYP51B1.Journal of inorganic biochemistry · 2020Article
- The label-free detection and distinction of CYP2C9-expressing and non-expressing cells by surface-enhanced Raman scattering substrates based on bimetallic AuNPs-AgNWs.RSC advances · 2019Article
- CW EPR parameters reveal cytochrome P450 ligand binding modes.Journal of inorganic biochemistry · 2018Article
- Spectroscopic studies of the cytochrome P450 reaction mechanisms.Biochimica et biophysica acta. Proteins and proteomics · 2018Review
- The tetrahydrobiopterin radical interacting with high- and low-spin heme in neuronal nitric oxide synthase - A new indicator of the extent of NOS coupling.Free radical biology & medicine · 2016Article
- Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Azoles and pyridines are commonly incorporated into small molecule inhibitor scaffolds that target cytochromes P450 (CYPs) as a strategy to increase drug binding affinity, impart isoform-dependent selectivity, and improve metabolic stability. Optical absorbance spectra of the CYP-inhibitor complex are widely used to infer whether these inhibitors are ligated directly to the heme iron as catalytically inert, low-spin (type II) complexes. Here, we show that the low-spin complex between a drug-metabolizing CYP2C9 variant and 4-(3-phenylpropyl)-1H-1,2,3-triazole (PPT) retains an axial water ligand despite exhibiting elements of "classic" type II optical behavior. Hydrogens of the axial water ligand are observed by pulsed electron paramagnetic resonance (EPR) spectroscopy for both inhibitor-free and inhibitor-bound species and show that inhibitor binding does not displace the axial water. A (15)N label incorporated into PPT is 0.444 nm from the heme iron, showing that PPT is also in the active site. The reverse type I inhibitor, LP10, of CYP125A1 from Mycobacterium tuberculosis, known from X-ray crystal structures to form a low-spin water-bridged complex, is found by EPR and by visible and near-infrared magnetic circular dichroism spectroscopy to retain the axial water ligand in the complex in solution.
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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.