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CW EPR parameters reveal cytochrome P450 ligand binding modes

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dc.contributor.authorLockart, Molly M.
dc.contributor.authorRodriguez, Carlo A.
dc.contributor.authorAtkins, William M.
dc.contributor.authorBowman, Michael K.
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.contributor.otherUniversity of Washington
dc.contributor.otherUniversity of Washington Seattle
dc.date.accessioned2023-09-28T19:13:42Z
dc.date.available2023-09-28T19:13:42Z
dc.date.issued2018
dc.description.abstractCytochrome P450 (CYP) monoxygenses utilize heme cofactors to catalyze oxidation reactions. They play a critical role in metabolism of many classes of drugs, are an attractive target for drug development, and mediate several prominent drug interactions. Many substrates and inhibitors alter the spin state of the ferric heme by displacing the heme's axial water ligand in the resting enzyme to yield a five-coordinate iron complex, or they replace the axial water to yield a nitrogen-ligated six-coordinate iron complex, which are traditionally assigned by UV-vis spectroscopy. However, crystal structures and recent pulsed electron paramagnetic resonance (EPR) studies find a few cases where molecules hydrogen bond to the axial water. The water-bridged drug-H2O-heme has UV-vis spectra similar to nitrogen-ligated, six-coordinate complexes, but are closer to "reverse type I" complexes described in older liteature. Here, pulsed and continuous wave (CW) EPR demonstrate that water-bridged complexes are remarkably common among a range of nitrogenous drugs or drug fragments that bind to CYP3A4 or CYP2C9. Principal component analysis reveals a distinct clustering of CW EPR spectral parameters for water-bridged complexes. CW EPR reveals heterogeneous mixtures of ligated states, including multiple directly-coordinated complexes and water-bridged complexes. These results suggest that water-bridged complexes are under-represented in CYP structural databases and can have energies similar to other ligation modes. The data indicates that water-bridged binding modes can be identified and distinguished from directly-coordinated binding by CW EPR.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationLockart, M. M., Rodriguez, C. A., Atkins, W. M., & Bowman, M. K. (2018). CW EPR parameters reveal cytochrome P450 ligand binding modes. In Journal of Inorganic Biochemistry (Vol. 183, pp. 157–164). Elsevier BV. https://doi.org/10.1016/j.jinorgbio.2018.02.021
dc.identifier.doi10.1016/j.jinorgbio.2018.02.021
dc.identifier.orcidhttps://orcid.org/0000-0003-3464-9409
dc.identifier.orcidhttps://orcid.org/0000-0002-3738-2474
dc.identifier.urihttps://ir.ua.edu/handle/123456789/11090
dc.languageEnglish
dc.language.isoen_US
dc.publisherElsevier
dc.subjectCytochrome P450
dc.subjectDrug binding
dc.subjectEPR
dc.subjectHYSCORE
dc.subjectX-RAY CRYSTALLOGRAPHY
dc.subjectLIVER-MICROSOMES
dc.subjectMETABOLIC STABILITY
dc.subjectINHIBITORY POTENCY
dc.subjectCRYSTAL-STRUCTURES
dc.subjectP450 INTERACTION
dc.subjectCLICK CHEMISTRY
dc.subjectHEME COMPLEXES
dc.subjectWATER BINDING
dc.subjectSPECTRA
dc.subjectBiochemistry & Molecular Biology
dc.subjectChemistry, Inorganic & Nuclear
dc.titleCW EPR parameters reveal cytochrome P450 ligand binding modesen_US
dc.typeArticle
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