# Structural Basis for Antiarrhythmic Drug Action

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $737,378

## Abstract

ABSTRACT
Voltage-gated sodium (Nav) channels initiate action potentials in the heart, and voltage-gated calcium (Cav) channels
initiate excitation-contraction coupling. They are related proteins with a common evolutionary ancestor, and they are
molecular targets for Class I and Class IV antiarrhythmic drugs (AADs) used in control of life-threatening cardiac
arrhythmias. The structural basis for AAD action is unknown. We have determined the crystal structure of an ancestral
bacterial Nav channel (NavAb) at 2.7 Å resolution and revealed the structural basis for voltage sensing, pore opening and
closing, ion selectivity, and slow inactivation. This structure also revealed fenestrations that lead laterally from the lipid
bilayer into the pore and provide an access pathway for entry of pore-blocking AADs. We constructed a Ca-selective form
of NavAb, termed CavAb, and used this construct to reveal the structural basis for Ca selectivity at atomic resolution. We
are now focusing on the structural basis for state-dependent block of Nav and Cav channels by AADs. CavAb is blocked
by all three structural subclasses of Class IV AADs in a state-dependent manner with nM affinity. We found that the
phenylalkylamine verapamil binds to a receptor site in the pore, at the inner end of the ion selectivity filter, and physically
blocks it. In contrast, amlodipine and other dihydropyridines bind at a site on the lipid-facing outer surface of the pore
module, at the interface between two voltage-sensing modules, and allosterically block the pore. These results reveal
drug-receptor complexes of Cav channels for the first time and set the stage for complete analysis of the mechanism of
state-dependent block of Nav and Cav channels at the atomic level. Our proposed experiments have three goals. 1. We
will build upon strong preliminary data to reveal the high-resolution structure of the therapeutically important
benzothiazepine diltiazem bound to its receptor site in the pore of CavAb, compare the chemistry of its binding to
verapamil, determine the role of fenestrations in state-dependent block of CavAb, and explore the effects of mutations that
substitute human residues in the AAD receptor site. 2. We will build on strong preliminary data to reveal the high-
resolution structures of Class 1 AADs such as lidocaine and flecainide bound to NavAb, differentiate among the binding
poses and receptor site conformations for Subclass 1A, 1B, and 1C AADs, determine the role of fenestrations in state-
dependent block of NavAb, and explore the effects of mutations that humanize the NavAb drug receptor. 3. Based on a
new homogeneous biochemical preparation, we will use cryo-electron microscopy and X-ray crystallography to determine
the structure of a mammalian cardiac Nav1.5 channel at high resolution, define the structural basis for its unique
physiological properties, and elucidate the structural basis for AAD block of Nav1.5 channels. Our results will be crucial
for understanding...

## Key facts

- **NIH application ID:** 9838773
- **Project number:** 5R01HL112808-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** WILLIAM A CATTERALL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $737,378
- **Award type:** 5
- **Project period:** 2012-04-06 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838773

## Citation

> US National Institutes of Health, RePORTER application 9838773, Structural Basis for Antiarrhythmic Drug Action (5R01HL112808-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838773. Licensed CC0.

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