# Enhancing olfactory receptor expression for biochemical studies of odorant-receptor interactions

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $688,557

## Abstract

Summary:
Title: Enhancing olfactory receptor expression for biochemical studies of odorant-
receptor interactions
Our sense of smell is mediated by olfactory receptors (ORs), which are the largest family
of G protein-coupled receptors (GPCRs). Some ORs also function outside the nose to
coordinate important physiology; OR function has been shown to be important in kidney,
skin, prostate, and in multiple cancer tissues. Despite groundbreaking advances in
delineating the structural basis of GPCR action, ORs remain among the most
unexplored class GPCRs in terms of structure, ligand binding and activation mechanism.
This is primarily because: 1) low expression of ORs in heterologous cell lines impedes
structure-function studies and 2) we lack small molecules that can potently activate and
inhibit OR function. In the past two years, Matsunami and Vaidehi have uncovered
amino acid sequence evolution and structural properties that contribute to OR
expression. Simultaneously, Matsunami and Manglik used engineered ORs with
enhanced expression to validate new approaches to purify ORs in detergents for
structural and biochemical studies. Building on these successes, we propose to address
fundamental challenges in OR expression and ligand discovery in iterative predict-test
cycles combining novel computational methods and experimental testing with two aims.
In Aim 1, we propose to engineer mutant ORs for six human ORs to enable
overexpression of these receptors for in vitro studies and tractability for large-scale
purification in detergents. In Aim 2, we will map OR ligand binding sites and discover
new high affinity agonists and antagonists using a combination of structural modeling,
ligand docking and biochemical experiments. We will also develop approaches to
determine structures of active ORs bound to odorants and G proteins by cryo-EM. The
outcome of the proposed work will provide new foundations to interrogate OR function
and widely available computational approaches to accelerate the OR field.

## Key facts

- **NIH application ID:** 10465009
- **Project number:** 1R01DC020353-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Aashish Manglik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $688,557
- **Award type:** 1
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465009

## Citation

> US National Institutes of Health, RePORTER application 10465009, Enhancing olfactory receptor expression for biochemical studies of odorant-receptor interactions (1R01DC020353-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10465009. Licensed CC0.

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