# Molecular Mechanisms Underlying Insect Odorant Receptor Function and Modulation

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2020 · $482,453

## Abstract

Project Summary
Insects are the primary vectors for many deadly diseases. Mosquitoes and other biting insects rely on their
exquisite sense of smell to identify and hone in on their human hosts. Consequently, one strategy to control the
transmission of insect-borne diseases is to target insect olfactory receptors, disrupt the initial detection of
human volatiles, and prevent insects from locating humans. The goal of developing potent insect repellents that
cripple host-seeking behavior is greatly facilitated by the unique molecular nature of insect olfactory receptors.
Insect olfactory receptors form a novel class of heteromeric ion channels comprised of two distinct subunits—a
highly divergent odorant receptor (OR) subunit that confers odorant specificity and a common Orco subunit,
that is virtually invariant amongst diverse insect species, reflecting its essential role in olfactory transduction.
Given the conserved and critical role that Orco plays in odor detection, it forms an ideal molecular target for a
much-needed new generation of insect repellents with the potential to halt the transmission of insect-borne
diseases. Unfortunately, as these receptors represent a unique specialization of insects and lack structural
homology to any other ion channel family, many of their most elementary structural and functional properties
have remained elusive, precluding sufficient mechanistic understanding to guide repellent design. To fill this
important void in the field, my lab recently determined the structure of an Orco homomeric channel using cryo-
electron microscopy, providing the first structural snapshot of an insect olfactory receptor. Building on this
advance and our expertise in odorant receptor biochemistry, we propose to elucidate the structure of Orco in
conditions that replicate its native environment: embedded within a lipid membrane (Aim 1) and assembled
with an OR to form a heteromeric channel (Aim 2), alone and in complex with synthetic agonists and odorants.
Revealing multiple structures of insect olfactory receptors in both apo and ligand bound states will provide
direct insight into the structural and mechanistic basis for their allosteric modulation. Together, the proposed
studies offer a unique and powerful inroad to the rational design of small-molecule repellents that disrupt odor
detection and host-seeking behavior in insect vectors of human disease.

## Key facts

- **NIH application ID:** 9886869
- **Project number:** 2R01AI103171-06
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Vanessa Ruta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $482,453
- **Award type:** 2
- **Project period:** 2013-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886869

## Citation

> US National Institutes of Health, RePORTER application 9886869, Molecular Mechanisms Underlying Insect Odorant Receptor Function and Modulation (2R01AI103171-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9886869. Licensed CC0.

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