An electron transfer competent structural ensemble of membrane-bound cytochrome P450 1A1 and cytochrome P450 oxidoreductase
| Autor: | Rebecca C. Wade, Prajwal P. Nandekar, Goutam Dev Mukherjee |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cytochrome QH301-705.5 Medicine (miscellaneous) Molecular Dynamics Simulation 010402 general chemistry urologic and male genital diseases digestive system 01 natural sciences General Biochemistry Genetics and Molecular Biology Article Electron Transport 03 medical and health sciences chemistry.chemical_compound Computational biophysics Cytochrome P-450 Enzyme System Protein Domains Cytochrome P-450 CYP1A1 Humans heterocyclic compounds Biology (General) Heme chemistry.chemical_classification biology organic chemicals Cell Membrane Cytochrome P450 Active site Monooxygenase respiratory system Ligand (biochemistry) 0104 chemical sciences enzymes and coenzymes (carbohydrates) 030104 developmental biology Enzyme Catalytic cycle chemistry Biochemistry biology.protein Molecular modelling General Agricultural and Biological Sciences Drug metabolism |
| Zdroj: | Communications Biology Communications Biology, Vol 4, Iss 1, Pp 1-13 (2021) |
| ISSN: | 2399-3642 |
| Popis: | Cytochrome P450 (CYP) heme monooxygenases require two electrons for their catalytic cycle. For mammalian microsomal CYPs, key enzymes for xenobiotic metabolism and steroidogenesis and important drug targets and biocatalysts, the electrons are transferred by NADPH-cytochrome P450 oxidoreductase (CPR). No structure of a mammalian CYP–CPR complex has been solved experimentally, hindering understanding of the determinants of electron transfer (ET), which is often rate-limiting for CYP reactions. Here, we investigated the interactions between membrane-bound CYP 1A1, an antitumor drug target, and CPR by a multiresolution computational approach. We find that upon binding to CPR, the CYP 1A1 catalytic domain becomes less embedded in the membrane and reorients, indicating that CPR may affect ligand passage to the CYP active site. Despite the constraints imposed by membrane binding, we identify several arrangements of CPR around CYP 1A1 that are compatible with ET. In the complexes, the interactions of the CPR FMN domain with the proximal side of CYP 1A1 are supplemented by more transient interactions of the CPR NADP domain with the distal side of CYP 1A1. Computed ET rates and pathways agree well with available experimental data and suggest why the CYP–CPR ET rates are low compared to those of soluble bacterial CYPs. Mukherjee, Nandekar and Wade investigate the structural arrangement of the complex between membrane-bound cytochrome P450 1A1 and NADPH-cytochrome P450 reductase. They find that upon binding to the reductase, the catalytic domain of cytochrome P450 1A1 reorients subject to the constraints of membrane binding, potentially explaining why the electron transfer rates between the proteins are low when compared to those of soluble bacterial cytochrome P450s. |
| Databáze: | OpenAIRE |
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