# Mechanisms of CLC Transporters and Channels:

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $25,320

## Abstract

The CLC (“Chloride Channel”) family encompasses two major ion-transport mechanisms: half
of CLC homologs are electrodiffusive ion channels, and half are secondary active transporters
that stoichiometrically exchange Cl– for H+. The occurrence of two mechanisms in one family
suggests they operate by variations on a common theme. Indeed, experimental results support
the hypothesis that CLC channels are “broken” transporters, in which tight coordination between
inner and outer gates is lost. Thus, subtle differences in protein conformational dynamics and ion
binding—and the interactions between them—can produce two different types of ion transport
behavior in proteins with the same secondary structure. Understanding the molecular basis of
these differences will inform our understanding of both CLC channels and transporters.
 As secondary active transporters, CLC transporters harness energy stored in one ion’s
electrochemical gradient (Cl– or H+) to pump the other ion against its gradient. This occurs through
tight coupling of protein conformational changes to ion binding and transport events. To develop
a fully integrated structural description of ion coupling in the CLC transport mechanism, this
project will combine complementary cutting-edge approaches, including cryo-electron microscopy
to determine high-resolution structures, double electron-electron resonance spectroscopy to
monitor the conformational state of the transporter under different conditions and with different
mutations, MD simulations to determine hydration pathways under various conditions, and
quantitative functional assays to connect structural dynamics to function.

## Key facts

- **NIH application ID:** 10383000
- **Project number:** 3R01GM113195-05S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Merritt C Maduke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $25,320
- **Award type:** 3
- **Project period:** 2016-09-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10383000

## Citation

> US National Institutes of Health, RePORTER application 10383000, Mechanisms of CLC Transporters and Channels: (3R01GM113195-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10383000. Licensed CC0.

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