# Structural basis for detoxification of environmental pollutants by native complexes of CYP2B family with its redox partners

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $234,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10147883
- **Project number:** 5R21ES030791-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Min Su
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,000
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147883

## Citation

> US National Institutes of Health, RePORTER application 10147883, Structural basis for detoxification of environmental pollutants by native complexes of CYP2B family with its redox partners (5R21ES030791-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10147883. Licensed CC0.

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