# Identification of potential drug binding sites within allosteric networks in cyclic nucleotide modulated channels

> **NIH NIH F32** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $67,582

## Abstract

PROJECT SUMMARY
Cyclic nucleotide modulated ion channels are a class of proteins that have important roles in many physiological
processes, including regulation of the heart, neuronal signaling, and pain perception. The discovery of new
drugs targeting different ion channels is notoriously difficult for a host of reasons, as the focus on traditional
orthosteric agonists and antagonists has been dominant. Overall, this proposal unifies genomic, functional, and
structural methods to reveal how specific allosteric interactions govern mechanistic function. The ability to detect
and isolate the function of networks of allosteric interactions can provide a more focused approach in the design
of allosteric drugs for cyclic nucleotide modulated channels. In the first aim, I will identify and classify allosteric
networks using coevolution analysis. Mutagenesis and quantitative electrophysiology measurements will be
used to probe how different residue positions contribute to requisite energetic coupling in channel gating. Next,
we will use this unique information to obtain novel channel transition states. The overall goal of this aim is to
define allosteric networks that functionally regulate cyclic nucleotide modulated ion channels, experimentally
validate these networks functionally, and use this information to obtain difficult-to-resolve conformational states.
In the second aim, I will seek to uncover unknown binding sites for known allosteric modulators of cyclic
nucleotide modulated ion channels. Using cryoEM, we will determine the structure of channels in complex with
established allosteric modulators and define their interaction with the allosteric networks in aim 1. We will
validate the binding site using mutagenesis and two electrode voltage clamp. This aim will demonstrate feasibility
of drug design strategies targeting allosteric networks.

## Key facts

- **NIH application ID:** 10537846
- **Project number:** 1F32GM145091-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Elizabeth Dione Kim
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 1
- **Project period:** 2022-08-24 → 2024-08-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537846

## Citation

> US National Institutes of Health, RePORTER application 10537846, Identification of potential drug binding sites within allosteric networks in cyclic nucleotide modulated channels (1F32GM145091-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10537846. Licensed CC0.

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