# Structural Determinants of Kappa Opioid Receptor Signaling

> **NIH NIH R35** · WASHINGTON UNIVERSITY · 2021 · $310,060

## Abstract

Project Summary/Abstract
G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and can signal
through multiple transducers, including heterotrimeric G protein and β-arrestins. Opioid receptors are GPCRs
whose role in pain sensation has made them primary drug targets for pain medications such as oxycodone and
morphine. However, opioids have exceptionally high abuse potential and often cause fatal side effects such as
respiratory arrest and death. The magnitude of these problems has led to a search for opioid alternatives to treat
pain and related conditions. Activation of opioid receptors activates downstream effectors, including multiple G
proteins (Gi1, Gi2, Gi3, GoA, GoB, Gz, and Ggustducin) and β-arrestins (β-arrestin1 and β-arrestin2). A major
gap is an incomplete understanding of how opioid receptors recognize different transducers and the functional
effects of signaling through each pathway. Kappa opioid receptor (KOR) has displayed promising therapeutic
potential because of its novel analgesic activity –drugs that target KOR do not lead to addiction or cause death
due to overdose as observed from mu opioid receptor agonists. Selective KOR antagonists have also been
pursued in clinical trials for the treatment of addiction and depression. The research in my lab is driven by the
overall hypothesis that large-scale structural determination studies of receptor-ligand/transducer complexes will
provide molecular-level insights into opioid receptor signaling, and facilitate the design and optimization of novel
ligand scaffolds that could be further developed into new drugs with desired behavior profile. By combining X-
ray crystallography, Cryo-EM, and molecular pharmacology, we will elucidate fundamental mechanisms of KOR
ligand selectivity, receptor activation and signaling. To do so, we will pursue the following main directions: (i)
identify structural determinants of ligand selectivity between different opioid receptors types, (ii) identify the
molecular basis for different G protein subtypes recognition, and (iii) identify structural features responsible for
arrestin-bound activating states. The long-term goal is to develop receptor-specific and pathway-selective probes
using structure-based drug discovery and study the function of individual opioid receptor signaling in vivo.

## Key facts

- **NIH application ID:** 10276901
- **Project number:** 1R35GM143061-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Tao Che
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $310,060
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276901

## Citation

> US National Institutes of Health, RePORTER application 10276901, Structural Determinants of Kappa Opioid Receptor Signaling (1R35GM143061-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10276901. Licensed CC0.

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