Structural basis for detoxification of environmental pollutants by native complexes of CYP2B family with its redox partners
CYP2B家族天然复合物及其氧化还原伙伴对环境污染物解毒的结构基础
基本信息
- 批准号:9979011
- 负责人:
- 金额:$ 19.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectApolipoproteinsArchitectureAryl Hydrocarbon HydroxylasesCYP2B4 geneCatalysisCell RespirationComplexComputer softwareCryoelectron MicroscopyCrystallizationCytochrome P450Cytochromes b5Data SetDetoxification ProcessDrug Metabolic DetoxicationDue ProcessEndoplasmic ReticulumEnvironmentEnvironmental PollutantsEnzymesExhibitsFamilyGenetic PolymorphismHealthHumanIceImageKnowledgeLengthLipidsLipoproteinsMalignant NeoplasmsMapsMembraneMembrane ProteinsMethodologyMethodsMolecularMolecular ConformationNMR SpectroscopyNegative StainingOrganophosphatesOxidation-ReductionOxidoreductasePathogenesisPesticidesPhospholipidsPlayPolychlorinated BiphenylsPreparationProcessProteinsRoleSAP-A ProteinSamplingStructural ModelsStructureSystemTestingTimeToxic effectX-Ray Crystallographybasebioaccumulationcontrast imagingelectron donorflexibilityhuman tissueimprovedinsightnanodisknanometer resolutionnanoparticleneurotoxicitynovelparticlepollutantpollutant interactionpolybrominated diphenyl etherprotein aggregationprotein complexreconstitutionreconstructionstoichiometrythree dimensional structure
项目摘要
ABSTRACT
Polychlorinated biphenyls and organophosphorus pesticides are ubiquitous environmental
pollutants. Bioaccumulation of these pollutants in human tissues is associated with cancer and
neurotoxicity. They are preferably metabolized by CYP2B subfamily enzymes. Essential to the
detoxification of these pollutants are the interactions of CYP2B enzymes with their redox
partners, cytochrome P450 oxidoreductase (POR) and cytochrome b5 (cyt b5). However, these
interactions in the context of endoplasmic reticulum (ER) membrane remain poorly understood.
In particular, the role of cyt b5 in the microsomal P450 system is enigmatic. It has been debated
for decades whether cyt b5 affects P450 activity as an electron donor or allosteric effector or
both. There is a clear knowledge gap between the important role of cyt b5 in P450 activity and
our understanding of its mechanism. Lack of understanding is in part due to the absence of 3D
structure of a native P450:b5 complex. It is highly challenging to obtain such a structure by
conventional methods like X-ray crystallography or NMR spectroscopy. Single-particle cryo-EM
has emerged as the method of choice for structural determination of multi-unit membrane
protein complexes where diffracting crystals are not available. We hypothesize that
determination of the 3D structure of a native CYP2B4-cyt b5 complex can be achieved using
single-particle cryo-EM in conjunction with novel sample preparations. We propose to test the
hypothesis and develop a much-needed cryo-EM method in two specific aims. In Aim 1, we will
prepare the CYP2B4-cyt b5 complex in novel nanoparticles and then determine its 3D structure
by single-particle cryo-EM in Aim 2. Successful completion of the two aims will not only provide
critical knowledge for understanding the role of cyt b5 in CYP2B4 activity, but also develop a
much-needed methodology for structural analysis of the native complexes of cyt b5 and POR
with many other P450 enzymes. Establishment of this methodology and availability of these
native complexes will be groundbreaking and provide a roadmap to interrogate the
mechanism(s) by which the microsomal P450 system detoxifies environmental pollutants.
摘要
项目成果
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