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Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9

The microsomal, membrane-bound, human cytochrome P450 (CYP) 2C9 is a liver-specific monooxygenase essential for drug metabolism. CYPs require electron transfer from the membrane-bound CYP reductase (CPR) for catalysis. The structural details and functional relevance of the CYP-membrane interaction a...

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Autores principales: Cojocaru, Vlad, Balali-Mood, Kia, Sansom, Mark S. P., Wade, Rebecca C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154944/
https://www.ncbi.nlm.nih.gov/pubmed/21852944
http://dx.doi.org/10.1371/journal.pcbi.1002152
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author Cojocaru, Vlad
Balali-Mood, Kia
Sansom, Mark S. P.
Wade, Rebecca C.
author_facet Cojocaru, Vlad
Balali-Mood, Kia
Sansom, Mark S. P.
Wade, Rebecca C.
author_sort Cojocaru, Vlad
collection PubMed
description The microsomal, membrane-bound, human cytochrome P450 (CYP) 2C9 is a liver-specific monooxygenase essential for drug metabolism. CYPs require electron transfer from the membrane-bound CYP reductase (CPR) for catalysis. The structural details and functional relevance of the CYP-membrane interaction are not understood. From multiple coarse grained molecular simulations started with arbitrary configurations of protein-membrane complexes, we found two predominant orientations of CYP2C9 in the membrane, both consistent with experiments and conserved in atomic-resolution simulations. The dynamics of membrane-bound and soluble CYP2C9 revealed correlations between opening and closing of different tunnels from the enzyme's buried active site. The membrane facilitated the opening of a tunnel leading into it by stabilizing the open state of an internal aromatic gate. Other tunnels opened selectively in the simulations of product-bound CYP2C9. We propose that the membrane promotes binding of liposoluble substrates by stabilizing protein conformations with an open access tunnel and provide evidence for selective substrate access and product release routes in mammalian CYPs. The models derived here are suitable for extension to incorporate other CYPs for oligomerization studies or the CYP reductase for studies of the electron transfer mechanism, whereas the modeling procedure is generally applicable to study proteins anchored in the bilayer by a single transmembrane helix.
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spelling pubmed-31549442011-08-18 Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9 Cojocaru, Vlad Balali-Mood, Kia Sansom, Mark S. P. Wade, Rebecca C. PLoS Comput Biol Research Article The microsomal, membrane-bound, human cytochrome P450 (CYP) 2C9 is a liver-specific monooxygenase essential for drug metabolism. CYPs require electron transfer from the membrane-bound CYP reductase (CPR) for catalysis. The structural details and functional relevance of the CYP-membrane interaction are not understood. From multiple coarse grained molecular simulations started with arbitrary configurations of protein-membrane complexes, we found two predominant orientations of CYP2C9 in the membrane, both consistent with experiments and conserved in atomic-resolution simulations. The dynamics of membrane-bound and soluble CYP2C9 revealed correlations between opening and closing of different tunnels from the enzyme's buried active site. The membrane facilitated the opening of a tunnel leading into it by stabilizing the open state of an internal aromatic gate. Other tunnels opened selectively in the simulations of product-bound CYP2C9. We propose that the membrane promotes binding of liposoluble substrates by stabilizing protein conformations with an open access tunnel and provide evidence for selective substrate access and product release routes in mammalian CYPs. The models derived here are suitable for extension to incorporate other CYPs for oligomerization studies or the CYP reductase for studies of the electron transfer mechanism, whereas the modeling procedure is generally applicable to study proteins anchored in the bilayer by a single transmembrane helix. Public Library of Science 2011-08-11 /pmc/articles/PMC3154944/ /pubmed/21852944 http://dx.doi.org/10.1371/journal.pcbi.1002152 Text en Cojocaru et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cojocaru, Vlad
Balali-Mood, Kia
Sansom, Mark S. P.
Wade, Rebecca C.
Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9
title Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9
title_full Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9
title_fullStr Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9
title_full_unstemmed Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9
title_short Structure and Dynamics of the Membrane-Bound Cytochrome P450 2C9
title_sort structure and dynamics of the membrane-bound cytochrome p450 2c9
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154944/
https://www.ncbi.nlm.nih.gov/pubmed/21852944
http://dx.doi.org/10.1371/journal.pcbi.1002152
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