Structure of human phagocyte NADPH oxidase in the resting state

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Abstract

Phagocyte oxidase plays an essential role in the first line of host defense against pathogens. It oxidizes intracellular NADPH to reduce extracellular oxygen to produce superoxide anions that participate in pathogen killing. The resting phagocyte oxidase is a heterodimeric complex formed by two transmembrane proteins NOX2 and p22. Despite the physiological importance of this complex, its structure remains elusive. Here we reported the cryo-EM structure of the functional human NOX2-p22 complex in nanodisc in the resting state. NOX2 shows a canonical 6-TM architecture of NOX and p22 has four transmembrane helices. M3, M4, and M5 of NOX2 and M1 and M4 helices of p22 are involved in the hetero-dimer formation. DH domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain (TMD), leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the dehydrogenase domain (DH) in a productive docked conformation.

Data availability

Cryo-EM maps and atomic coordinate of the NOX2-p22-7D5-TP1170 complex have been deposited in the EMDB and PDB under the ID codes EMDB: EMD-34389 and PDB: 8GZ3.

The following data sets were generated

1. Rui Liu and Lei Chen
(2022) Structure of human NOX2 resting state
PDB, 8GZ3.

https://www.rcsb.org/structure/8GZ3
1. Rui Liu and Lei Chen
(2022) Structure of human NOX2 in the resting state
EMDB, EMD-34389.

https://www.ebi.ac.uk/emdb/EMD-34389

Article and author information

Author details

Rui Liu

Institute of Molecular Medicine, Peking University, Beijing, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3758-6493
Kangcheng Song

Institute of Molecular Medicine, Peking University, Beijing, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7932-2202
Jing-Xiang Wu

Institute of Molecular Medicine, Peking University, Beijing, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9851-0065
Xiao-Peng Geng

Institute of Molecular Medicine, Peking University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Liming Zheng

College of Chemistry and Molecular Engineering, Peking University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Xiaoyin Gao

College of Chemistry and Molecular Engineering, Peking University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Hailin Peng

College of Chemistry and Molecular Engineering, Peking University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Lei Chen

Institute of Molecular Medicine, Peking University, Beijing, China

For correspondence
chenlei2016@pku.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7619-8311

Funding

National Key Research and Development Program of China (2022YFA1300088)

Lei Chen

National Natural Science Foundation of China (91957201,31870833,31821091,52021006)

Hailin Peng
Lei Chen

Beijing National Laboratory for Molecular Sciences (BNLMS-CXTD-202001)

Hailin Peng

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.