# Structural Dynamics of Multi-drug Transporters

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $235,583

## Abstract

Bacterial homeostasis and survival is critically dependent on defense mechanisms that modify,
deactivate, or extrude cytotoxic molecules such as antiseptics and antibiotics, which passively
cross the membrane down their concentration gradients. One ubiquitous and highly conserved
mechanism entails the expression of polyspecific membrane transporters, referred to as multidrug
(MDR) transporters, which harness the Gibbs energy stored in ion electrochemical gradients to
power the uphill vectorial clearance of a broad spectrum of cytotoxic molecules. Energy-coupled
isomerization of the transporter between multiple intermediates enables alternating access of the
substrate binding site from one side of the membrane to the other. Defining the structural elements
mediating alternating access and decoding the mechanism of energy conversion in a lipid bilayer-like environment are exciting frontiers in the field and critical for defining transport mechanisms.
This proposal will continue support of a productive research program focused on addressing these
questions for two families of ion-coupled MDR transporters that have been implicated in clinical
drug resistance. Our approach capitalizes on the tool kit of EPR spectroscopy in the context of
high resolution structures, is informed by functional studies, and is contextualized through
collaborative molecular modeling efforts. Aim 1 seeks to elucidate principles of ion-substrate
coupling, identify residues critical for ion and substrate binding, and reveal how specific
transporter-lipids interactions shape the energy landscape of conformational changes in two
archetypes of the Multidrug and Toxin Extrusion (MATE) family of multidrug transporters. Aim 2
seeks to identify conserved elements of alternating access and ion-substrate coupling for the
major facilitator (MFS) family of MDR transporters. We will test a detailed mechanism of ligand-dependent conformational changes, developed in the previous funding period, that integrate ion
coupling with specific lipid interactions in the context of a well-established transport model.
Together, the two aims will illuminate mechanistic principles for families of transporters implicated
in the phenomenon of drug resistance and basic bacterial defense strategies.

## Key facts

- **NIH application ID:** 10145006
- **Project number:** 5R01GM077659-14
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Hassane S Mchaourab
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $235,583
- **Award type:** 5
- **Project period:** 2006-03-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145006

## Citation

> US National Institutes of Health, RePORTER application 10145006, Structural Dynamics of Multi-drug Transporters (5R01GM077659-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10145006. Licensed CC0.

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