# Understanding membrane proteins’ allosteric modulation with cryo-EM

> **NIH NIH R35** · NEW YORK UNIVERSITY · 2024 · $410,550

## Abstract

Project Summary/Abstract
Our laboratory is primarily focused on elucidating the molecular mechanisms integral to transmembrane
receptor function and modulation of their signaling output. We employ cryo-electron microscopy (cryo-EM) in
conjunction with advanced classification methodologies such as manifold embedding, modeling, and molecular
dynamics to investigate how ligand binding influences conformational equilibria and signaling bias. Our
research encompasses various systems, enabling us to examine the impact of different ligand types on ion
channel gating and G protein-coupled receptor (GPCR) activation.
Our longstanding research interest lies in receptors vital to heart and skeletal muscle function. We are
investigating the mechanisms and modulation of ryanodine receptors (RyR) and beta-adrenergic receptors,
which play a crucial role in cardiac and skeletal muscle functionality. Our objective is to elucidate how small
molecules, protein regulators, and ions shape the conformational energy landscape of these receptors. This
knowledge is critical for understanding calcium signaling regulation and for designing innovative therapeutics to
address cardiac and muscle disorders.
Another research interest is exploring lipid-triggered gating of mechanosensitive channels from the MscS
family, a model system for membrane tension-sensing. This research can provide valuable insights into the
fundamental principles governing ion channel gating and the role of lipid-protein interactions in this process.
Our research approach combines cryo-EM, advanced image classification techniques, residue network
analysis, and molecular dynamics simulations to mechanistically delineate allosteric pathways. We
subsequently validate proposed models using biophysical techniques such as single-channel measurements,
hydrogen-deuterium exchange mass spectrometry (HDX-MS), and mutagenesis.
Our long-term goal is to significantly enhance our molecular understanding of receptor activation and allosteric
modulation. Advancement in this field could potentially pave the way for the design of small molecule allosteric
modulators with precise control over their effects on their targets, thus aiding in the development of drugs with
minimized side effects.
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## Key facts

- **NIH application ID:** 10842901
- **Project number:** 2R35GM133598-07
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Amedee des Georges
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,550
- **Award type:** 2
- **Project period:** 2019-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842901

## Citation

> US National Institutes of Health, RePORTER application 10842901, Understanding membrane proteins’ allosteric modulation with cryo-EM (2R35GM133598-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842901. Licensed CC0.

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