- Article
- Published:
- Xin Wang (王鑫)2 na1,
- Xuebo Quan (全学波)3 na1,
- Stephen T. Ferguson2,
- Dong Liu (刘东)1,4,
- Jiawei Chen (陈嘉伟)1,5,
- Sai Wang (王赛)6,
- Simin Liang (梁思敏)2,
- Gaoxingyu Huang (黄高兴宇)6,
- Kai Huang (黄恺) ORCID: orcid.org/0000-0001-8400-93413,
- Feng Liu (柳峰) ORCID: orcid.org/0000-0003-3517-98242 &
- …
- Xiaojing Pan (潘孝敬) ORCID: orcid.org/0000-0003-1882-53611
Nature (2026) Cite this article
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Abstract
Ionotropic receptors (IRs) are essential for insect olfaction, enabling the detection of carboxylic acids, amines, moisture, and temperature cues that mediate critical behaviors, including mosquito host-seeking 1,2. However, the structural mechanisms underlying ligand specificity and channel activation in these receptors remain unclear. Here, we report cryo-electron microscopy (cryo-EM) structures and functional validation of the IR8a-IR75k complex from the malaria mosquito Anopheles stephensi, a carboxylic acid detector, captured in four states: the ligand-free full-length closed form (apo state), the ligand induced full-length open state, and the nonanoic acid (NA)- and octanoic acid (OA)-bound extracellular domains. These structures reveal a dynamic ligand-binding pocket in IR75k, in which specificity is determined by alkyl chain length and carboxylate geometry. Ligand binding triggers closure of IR75k’s bilobed ligand binding domain (LBD), and this conformational change propagates through conserved mechanical linkers to the transmembrane domain (TMD), functioning as a molecular lever that dilates the pore via outward displacement of transmembrane helices. This gating mechanism was further corroborated by molecular dynamics simulations and electrophysiology. These insights provide an atomic resolution view of IR mediated host detection in mosquitoes and establish a foundation for the rational design of next generation mosquito control strategies targeting host-seeking behavior.
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Supplementary information
Supplementary Information (download PDF )
This file contains Supplementary Figs. 1-3 and Supplementary Table 1. Supplementary Fig. 1: Sequence alignment of IR75k among mosquitoes; Supplementary Fig.2: Uncropped western blot images of IR8a-IR75k variants for Extended Data Fig. 8h; Supplementary Fig.3: Sequence alignment of IR8a from different mosquito species; Supplementary Table 1: Reliability and reproducibility checklist for molecular dynamics simulations.
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Supplementary Video 1 (download MP4 )
Molecular dynamics simulation of the NA-bound IR8a-IR75k complex under an external electric field. The simulation was initiated from our experimental determined cryo-EM structure of the NA-bound IR8a-IR75k complex. The complex was embedded in a lipid bilayer and subjected to an external electric field of 0.015 V/nm along the membrane. Sodium ion (green sphere) is shown permeating the channel in a partially dehydrated state during the simulation.
Supplementary Video 2 (download MP4 )
Molecular dynamics simulation of the apo state IR8a-IR75k complex under an external electric field. The simulation was initiated from our experimentally determined cryo-EM structure of the apo state IR8a-IR75k complex under the same simulation conditions as Supplementary Video 1. No sodium ion permeation through the channel was observed during the simulation, supporting the conclusion that ligand binding is required to trigger the conformational cascade necessary for channel gating and sodium ion permeation.
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Xu, L., Wang, X., Quan, X. et al. Structural basis of ligand recognition and gating in mosquito IRs. Nature (2026). https://doi.org/10.1038/s41586-026-11239-3
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DOI: https://doi.org/10.1038/s41586-026-11239-3