# Structural mechanisms for gating of bacterial cyclic nucleotide-gated ion channels

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $396,383

## Abstract

Cyclic nucleotide-regulated ion channels are exquisite molecular machines that
underlie important physiological functions. Cyclic nucleotide-gated (CNG) channels
generate the primary electrical response to light in photoreceptors and to odorant in
olfactory receptors. The related hyperpolarization-activated cyclic nucleotide-gated
(HCN) channels underlie the pacemaker activity of the heart and many neurons in the
brain. These cation selective channels are opened by the direct binding of cyclic
nucleotides (cAMP and cGMP) to an intracellular domain of the channel. Our goal is to
reveal the molecular mechanism for this allostery in CNG channels. Our approach will
be to study bacterial CNG channels as a model system for the eukaryotic channels
because of the huge advantages they provide for our biochemical methods . We will
leverage the power of four different methodologies to determine the structure,
conformational heterogeneity, and dynamics of these channels: 1) cryoelectron
microscopy (cryo-EM), 2) double electron-electron resonance (DEER), 3) microfluidic
rapid freeze quench (µRFQ) in combination with DEER, and 4) Rosetta-based molecular
modeling. The proposal includes four investigators who are pioneers in each of these
methods. The use of all four methods on the same ion channel under the same
conditions is synergistic and ultimately will lead to a comprehensive structural and
energetic model for the allostery of this channel. Ultimately a molecular understanding
of these channels would inform not only the physiology and pathophysiology of the heart
and brain, but also the general mechanisms for allosteric control of many enzymes.

## Key facts

- **NIH application ID:** 10224689
- **Project number:** 5R01GM127325-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** William N Zagotta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,383
- **Award type:** 5
- **Project period:** 2018-09-20 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224689

## Citation

> US National Institutes of Health, RePORTER application 10224689, Structural mechanisms for gating of bacterial cyclic nucleotide-gated ion channels (5R01GM127325-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224689. Licensed CC0.

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