TY - JOUR TI - Structure of human phagocyte NADPH oxidase in the resting state AU - Liu, Rui AU - Song, Kangcheng AU - Wu, Jing-Xiang AU - Geng, Xiao-Peng AU - Zheng, Liming AU - Gao, Xiaoyin AU - Peng, Hailin AU - Chen, Lei A2 - Brunger, Axel T A2 - Dötsch, Volker A2 - Pick, Edgar VL - 11 PY - 2022 DA - 2022/11/22 SP - e83743 C1 - eLife 2022;11:e83743 DO - 10.7554/eLife.83743 UR - https://doi.org/10.7554/eLife.83743 AB - 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 heterodimer formation. Dehydrogenase (DH) domain of NOX2 in the resting state is not optimally docked onto the transmembrane domain, leading to inefficient electron transfer and NADPH binding. Structural analysis suggests that the cytosolic factors might activate the NOX2-p22 complex by stabilizing the DH in a productive docked conformation. KW - NOX KW - NOX2 KW - p22 KW - CGD KW - CYBA KW - CYBB KW - NADPH oxidase JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -