# Structural Dynamics of Active Transporters

> **NIH NIH R35** · VANDERBILT UNIVERSITY · 2024 · $562,773

## Abstract

The long-term goal of the PI’s research program is to illuminate the structure, dynamics and
mechanistic principles that underpin active efflux of solutes, often of impressive size such as
protein domains, across cell membranes. Clinical multidrug resistance (MDR) in the treatment of
bacterial and fungal infections, and chemotherapy of neoplasms can be associated with
overexpression of membrane-embedded efflux pumps, collectively referred to as MDR
transporters, that selectively extrude cytotoxic molecules from the cell. MDR transporters harness
the free energy of ATP hydrolysis or that stored in electrochemical gradients to power a
conformational cycle that drives the energetically uphill vectorial translocation of substrates. The
cycle entails the energy-coupled isomerization of the transporter between multiple intermediates
thereby executing alternating access of the substrate binding site. Defining the structural elements
mediating alternating access and decoding the mechanism of energy conversion in a lipid bilayer
environment are central questions in the field and critical for elucidating transport mechanisms.
This MIRA proposal will continue support of two established, productive research programs
focused on addressing these questions for ATP binding cassette (ABC) and Multidrug and Toxin
Extrusion (MATE) transporters. Our innovative experimental blueprint capitalizes on recent
transformational advances in machine learning protein structure prediction, state of the art
electron paramagnetic spectroscopy (EPR) tools in the context of high resolution cryoEM
structures. Project 1, motivated and grounded in the contribution of the PI’s group, seeks to
decipher ion-substrate coupling, to define conserved and divergent elements of alternating
access, and to reveal specific transporter-lipids interactions that shape the energy landscape of
conformational changes in MATE transporters. Project 2 will expand a long-standing investigation
of energy transduction and alternating access ABC efflux transporters in three archetypes that
represent a spectrum of energy conversion and substrate size. The two projects will illuminate
mechanistic principles for families of transporters implicated in the phenomena of drug resistance
and basic bacterial defense strategies.

## Key facts

- **NIH application ID:** 10772347
- **Project number:** 1R35GM152382-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Hassane S Mchaourab
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $562,773
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772347

## Citation

> US National Institutes of Health, RePORTER application 10772347, Structural Dynamics of Active Transporters (1R35GM152382-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10772347. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*