# Structural mechanism of polymodal TRP channel activation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $404,149

## Abstract

Project Summary
Capsaicin- and heat-activated TRPV1 ion channel is a primary nociceptor for both chemical and
thermal stimuli, hence an attractive target for pain medication. Despite the availability of cryo-EM
structures of TRPV1 at up-to-2.9 Å resolutions, molecular mechanisms underlying TRPV1 activation
remains unclear. A major limitation for obtaining mechanistic information from the cryo-EM structures
is the general lack of resolution to determine side-chain orientation and the associated atomic
interaction. We recently demonstrated that the limitation could be overcome by combining Rosetta
structural prediction with site-specific functional tests such as thermodynamic mutant cycle analysis
that serve to constrain, validate, and improve structure prediction. Using this iterative approach, in
combination with site-specific fluorescence recordings including FRET and patch fluorometry, our
study aims to identify functional interactions in the capsaicin-binding domain and the outer pore and,
more importantly, to reveal dynamic changes of these interactions during capsaicin- and heat-induced
activation. We will take particular advantage of the fluorescent unnatural amino acid (FUAA)
incorporation method to introduce a small fluorophore to the channel’s moving parts. Our goal is to
elucidate structural mechanisms for key molecular interactions that mediate chemical and thermal
activation, thus providing a molecular framework to guide pharmaceutical intervention.

## Key facts

- **NIH application ID:** 9963426
- **Project number:** 5R01NS103954-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** VLADIMIR M YAROV-YAROVOY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,149
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963426

## Citation

> US National Institutes of Health, RePORTER application 9963426, Structural mechanism of polymodal TRP channel activation (5R01NS103954-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963426. Licensed CC0.

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