Targeting the Universal Insect Olfactory Coreceptor: Structural Basis for the Discovery of Next-generation Behavioral Disruptors

• Grant number: 25/29018-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2026
• End date: July 31, 2029
• Field of knowledge: Interdisciplinary Subjects
• Principal Investigator: Rafael Junqueira Borges
• Grantee: João Victor Teixeira Gomes
• Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 25/12632-9 - LIGAND-AI: artificial intelligence and small molecule drug discovery - an experimental and data roadmap, AP.TEM

Abstract

Insects rely on olfaction to interpret chemical cues essential for survival, making the olfactory system a strategic target for vector and pest control. Central to this system is the olfactory coreceptor (Orco), a highly conserved protein that is indispensable for the function of all odorant receptors (ORs). Despite recent structural advances, the mechanisms by which small molecules regulate Orco activation remain poorly understood. A recent, yet unpublished, structure of Orco in complex with the agonist VUAA4 revealed a pore-proximal allosteric site, along with associated lipids that may regulate ion channel activity. This project integrates structural biology, native mass spectrometry, molecular dynamics, and AI-assisted ligand discovery and optimization to elucidate the principles governing Orco activation and to leverage this knowledge to develop allosteric modulators that disrupt insect olfaction, thereby establishing a solid mechanistic foundation for innovative vector control strategies. (AU)