Allosteric Interactions in Human Cytochrome P450 CYP3A4: The Role of Phenylalanine 213

Biochemistry
Ilia G DenisovStephen G Sligar

Abstract

The role of Phe213 in the allosteric mechanism of human cytochrome P450 CYP3A4 was studied using a combination of progesterone (PGS) and carbamazepine (CBZ) as probe substrates. We expressed, purified, and incorporated into POPC Nanodiscs three mutants, F213A, F213S, and F213Y, and compared them with wild-type (WT) CYP3A4 by monitoring spectral titration, the rate of NADPH oxidation, and steady-state product turnover rates with pure substrates and substrate mixtures. All mutants demonstrated higher activity with CBZ, lower activity with PGS, and a reduced level of activation of CBZ epoxidation by PGS, which was most pronounced in the F213A mutant. Using all-atom molecular dynamics simulations, we compared the dynamics of WT CYP3A4 and the F213A mutant incorporated into the lipid bilayer and the effect of the presence of the PGS molecule at the allosteric peripheral site and evaluated the critical role of Phe213 in mediating the heterotropic allosteric interactions in CYP3A4.

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Jan 14, 1997·Biochemistry·Y F UengF P Guengerich
Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·G R Harlow, J R Halpert
May 23, 2000·Biochemistry·N A HoseaF P Guengerich
Jul 27, 2001·Current Drug Metabolism·W Tang, R A Stearns
Mar 20, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stephen M FowlerRobert J Riley
Mar 18, 2004·Journal of the American Chemical Society·I G DenisovS G Sligar
Jul 20, 2004·The Journal of Biological Chemistry·Jason K YanoEric F Johnson
Sep 17, 2004·Archives of Biochemistry and Biophysics·Bradley J BaasStephen G Sligar
Apr 16, 2005·Annual Review of Pharmacology and Toxicology·William M Atkins
Oct 14, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aleksandra GaletinJ Brian Houston
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Jun 10, 2006·The Journal of Biological Chemistry·Ilia G DenisovStephen G Sligar
Oct 6, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Chuang LuSuresh K Balani
Jan 11, 2007·The Journal of Biological Chemistry·Ilia G DenisovStephen G Sligar
Jul 26, 2007·The Journal of Biological Chemistry·Ilia G DenisovStephen G Sligar
Dec 7, 2007·The Journal of Biological Chemistry·Samuel L CollomGrover P Miller
Dec 22, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ping KangMaria Almira Correia
Dec 2, 2008·Expert Opinion on Drug Metabolism & Toxicology·Dmitri R Davydov, James R Halpert
Jun 30, 2009·Archives of Biochemistry and Biophysics·Daniel J FrankStephen G Sligar
Jul 6, 2010·Biochemical and Biophysical Research Communications·Yelena V GrinkovaStephen G Sligar
Aug 6, 2010·Biochimica Et Biophysica Acta·Ilia G Denisov, Stephen G Sligar
Oct 19, 2010·BMC Structural Biology·Demet SirimJürgen Pleiss
Dec 15, 2010·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Harshica FernandoDmitri R Davydov
Dec 24, 2010·The Journal of Biological Chemistry·Daniel J FrankStephen G Sligar
Dec 6, 2011·The Journal of Physical Chemistry. B·Joseph B LimJeffery B Klauda
Dec 24, 2011·The Journal of Biological Chemistry·Dmitri R DavydovJames R Halpert
Nov 14, 2012·Journal of Chemical Information and Modeling·K VanommeslaegheA D MacKerell
Nov 14, 2012·Journal of Chemical Information and Modeling·K Vanommeslaeghe, A D MacKerell
Mar 12, 2013·Methods in Molecular Biology·A LuthraS G Sligar
Apr 17, 2013·Journal of Medicinal Chemistry·Irina F Sevrioukova, Thomas L Poulos
Oct 29, 2013·Journal of the American Chemical Society·Michael C GregoryStephen G Sligar
Dec 5, 2013·Biochemical and Biophysical Research Communications·Yogan KhatriStephen G Sligar
May 9, 2014·Current Topics in Medicinal Chemistry·Irina F Sevrioukova, Thomas L Poulos
Mar 18, 2015·Biochemistry·Ilia G DenisovStephen G Sligar
Jun 28, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Tao Zhang

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Citations

Jul 17, 2020·Pharmaceutical Biology·Yang LiHaiping Wang
Nov 10, 2020·Protein Science : a Publication of the Protein Society·Stephen G Sligar, Ilia G Denisov
Nov 17, 2020·Archives of Biochemistry and Biophysics·Bikash DangiDmitri R Davydov
Dec 17, 2019·Biophysical Journal·Asuka A OrrPhanourios Tamamis
Apr 23, 2021·Journal of Chemical Information and Modeling·Junhao LiYaoquan Tu
Jun 3, 2021·International Journal of Molecular Sciences·Irina F Sevrioukova
May 28, 2021·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Jacqueline Wen Hui LeowEric Chun Yong Chan
Aug 31, 2021·RSC Chemical Biology·Samson A SouzaHo Leung Ng
Sep 21, 2021·Chembiochem : a European Journal of Chemical Biology·Libo Zhang, Qian Wang

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