43EG

Cryo-EM structure of Anopheles stephensi IR8a-IR75k receptor with nonanoic acid

Summary for 43EG

• Entry DOI: 10.2210/pdb43eg/pdb
• EMDB information: 81813
• Descriptor: Ionotropic receptor coreceptor Ir8a, Ionotropic glutamate receptor C-terminal domain-containing protein, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: ion channel, membrane protein
• Biological source: Anopheles stephensi (Asian malaria mosquito); More
• Total number of polymer chains: 4
• Total formula weight: 360543.66

Authors

Xu, L.,Pan, X.J. (deposition date: 2026-06-28, release date: 2026-10-28, Last modification date: 2026-11-04)

Primary citation

Xu, L.,Wang, X.,Quan, X.,Ferguson, S.T.,Liu, D.,Chen, J.,Wang, S.,Liang, S.,Huang, G.,Huang, K.,Liu, F.,Pan, X.
Structural basis of ligand recognition and gating in mosquito IRs.
Nature, 2026

PubMed 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 . 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.

PubMed: 42875027
DOI: 10.1038/s41586-026-11239-3

Experimental method

ELECTRON MICROSCOPY (3.33 Å)