# High-resolution crystallographic and functional studies of K+ channel function.

> **NIH NIH R01** · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · 2021 · $305,967

## Abstract

K+ channels are key regulators of cell excitability in the nervous system, skeletal, smooth and cardiac muscle and
secretory glands. Therefore, it is not surprising that dysfunction of K+ channels are the underlie cause of
uncountable human pathologies, such as: neurological disorders, cardiac diseases and diabetes. For this reason,
it is extremely important to understand at the atomic level the properties of K+ channels that determine cell
excitability. Understanding ion selectivity, permeation and gating at atomic detail will allow us
to identify highly-specific therapeutic agents that can recognize with precision a specific
channel's kinetic state that need to be regulated to correct a given channelopathy. It follows that
for two decades, functional, structural and computational studies, performed on the KcsA-closed structure, have
improved our understanding of how the structure defines the function of K+ channels. Recently, we have made
two important scientific contributions: the first atomic-resolution description of KcsA's minimal kinetic cycle
and the quantification of the energetics associated with each kinetic cycle reaction. However, important
unanswered questions remain, mostly due to our inability to conduct simultaneous structural and functional
studies in: 1 ) the open-state of the channel 2) mutants of the highly conserved glycine residues in the selectivity
filter, which are known to affect inactivation gating, ion selectivity and/or ion binding in the closed and open
states of the channel, 3) tandem-tetramers to dissect cooperativity of ion channel function, and 4) mutants that
dissect the non-conductive open states of KcsA by precisely uncoupling activation-gate opening from the onset
of ion permeation/inactivation at the selectivity filter. Consequently, we propose the following Specific Aims: 1)
To characterize the structure-function correlations between the selectivity filter, ion occupancy and conduction
properties of KcsA “trapped” with its activation gate open 2) To determine the structure-function correlations of
KcsA subunit cooperativity using tandem hetero-tetramers 3) To understand the role of KcsA's allosteric
coupling on the onset of ion permeation, C-type inactivation and ion selectivity and 4) To understand the
structural and functional roles of the glycine residues within the K+ channel selectivity filter. The novelty of our
experimental approaches, together with our vast experience working with ion channels, fully qualifies us to
perform the proposed project. Finally, the completion of this project will bring us closer to a complete atomistic
understanding of ion-channel function, allowing us to identify ion-channels kinetic intermediates more suitable
as pharmaceutical targets for the next generation of more specific and safer therapeutic drugs.

## Key facts

- **NIH application ID:** 10197146
- **Project number:** 5R01GM097159-09
- **Recipient organization:** TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
- **Principal Investigator:** Luis Gonzalo Cuello
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $305,967
- **Award type:** 5
- **Project period:** 2012-04-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197146

## Citation

> US National Institutes of Health, RePORTER application 10197146, High-resolution crystallographic and functional studies of K+ channel function. (5R01GM097159-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10197146. Licensed CC0.

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