8XLH

Structure of chimeric RyR-I4657M/G4819E

This is a non-PDB format compatible entry.

Summary for 8XLH

• Entry DOI: 10.2210/pdb8xlh/pdb
• EMDB information: 38448 60899
• Descriptor: Ryanodine receptor 1, Peptidyl-prolyl cis-trans isomerase FKBP1B, Calmodulin-1, ... (7 entities in total)
• Functional Keywords: ryanodine receptor, ion channel, membrane protein
• Biological source: Oryctolagus cuniculus (rabbit); More
• Total number of polymer chains: 12
• Total formula weight: 2380260.51

Authors

Lin, L.,Wang, C.,Wang, W.,Jiang, H.,Yuchi, Z. (deposition date: 2023-12-26, release date: 2024-10-30)

Primary citation

Lin, L.,Wang, C.,Wang, W.,Jiang, H.,Murayama, T.,Kobayashi, T.,Hadiatullah, H.,Chen, Y.S.,Wu, S.,Wang, Y.,Korza, H.,Gu, Y.,Zhang, Y.,Du, J.,Van Petegem, F.,Yuchi, Z.
Cryo-EM structures of ryanodine receptors and diamide insecticides reveal the mechanisms of selectivity and resistance.
Nat Commun, 15:9056-9056, 2024

PubMed Abstract: The resistance of pests to common insecticides is a global issue that threatens food production worldwide. Diamide insecticides target insect ryanodine receptors (RyRs), causing uncontrolled calcium release from the sarcoplasmic and endoplasmic reticulum. Despite their high potency and species selectivity, several resistance mutations have emerged. Using a chimeric RyR (chiRyR) approach and cryo-electron microscopy (cryo-EM), we investigate how insect RyRs engage two different diamide insecticides from separate families: flubendiamide, a phthalic acid derivative, and tetraniliprole, an anthranilic compound. Both compounds target the same site in the transmembrane region of the RyR, albeit with different poses, and promote channel opening through coupling with the pore-forming domain. To explore the resistance mechanisms, we also solve two cryo-EM structures of chiRyR carrying the two most common resistance mutations, I4790M and G4946E, both alone and in complex with the diamide insecticide chlorantraniliprole. The resistance mutations perturb the local structure, directly reducing the binding affinity and altering the binding pose. Our findings elucidate the mode of action of different diamide insecticides, reveal the molecular mechanism of resistance mutations, and provide important clues for the development of novel pesticides that can bypass the resistance mutations.

PubMed: 39428398
DOI: 10.1038/s41467-024-53490-0

Experimental method

ELECTRON MICROSCOPY (3.62 Å)