Ultrastructure and ligand-gating of the human GluD1 receptor
- 1Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine , Baltimore, MD 21205 ,
- 2Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine , Baltimore, MD 21205 ,
Abstract
The delta-type ionotropic glutamate receptors (iGluRs) GluD1 and GluD2 are ligand-gated ion channels that are fundamental for regulating both excitatory and inhibitory synapses. Rising evidence points to the role of GluD1 in the development of neurological diseases. However, the ultrastructure of human GluD1 (hGluD1) and the molecular basis for its ligand-gating remain unclear. Here, we define the ultrastructure of hGluD1 with cryo-electron microscopy (cryoEM) and through single channel bilayer recordings, show evidence of its ligand-gating capabilities. While hGluD1 exhibits a non-swapped architecture, it contains conserved iGluR moieties that enable ligand-gating, such as a ligand-binding domain (LBD) tethered to a transmembrane ion channel. Binding of the neurotransmitter γ-aminobutyric acid (GABA) or D-serine to the LBD enables cation influx through the hGluD1 ion channel in a concentration-dependent manner. Our findings delineate the molecular architecture and function of hGluD1, provide foundations for understanding patient mutations in hGluD1, and will invigorate therapeutic development against hGluD1.
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BibTeX
@article{mondal2026ultrastructure,
title = {{Ultrastructure and ligand-gating of the human GluD1 receptor}},
author = {Anish Kumar Mondal and Haobo Wang and Mae G Weaver and Iris Zheng and Nikita Kormshchikov and Fairine Ahmed and Edward C Twomey},
journal = {PNAS Nexus},
year = {2026},
month = oct,
doi = {10.1093/pnasnexus/pgag372},
url = {https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag372/9003600},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Ultrastructure and ligand-gating of the human GluD1 receptor
AU - Anish Kumar Mondal
AU - Haobo Wang
AU - Mae G Weaver
AU - Iris Zheng
AU - Nikita Kormshchikov
AU - Fairine Ahmed
AU - Edward C Twomey
PY - 2026
DA - 2026/10/28
JO - PNAS Nexus
DO - 10.1093/pnasnexus/pgag372
UR - https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag372/9003600
AB - The delta-type ionotropic glutamate receptors (iGluRs) GluD1 and GluD2 are ligand-gated ion channels that are fundamental for regulating both excitatory and inhibitory synapses. Rising evidence points to the role of GluD1 in the development of neurological diseases. However, the ultrastructure of human GluD1 (hGluD1) and the molecular basis for its ligand-gating remain unclear. Here, we define the ultrastructure of hGluD1 with cryo-electron microscopy (cryoEM) and through single channel bilayer recordings, show evidence of its ligand-gating capabilities. While hGluD1 exhibits a non-swapped architecture, it contains conserved iGluR moieties that enable ligand-gating, such as a ligand-binding domain (LBD) tethered to a transmembrane ion channel. Binding of the neurotransmitter γ-aminobutyric acid (GABA) or D-serine to the LBD enables cation influx through the hGluD1 ion channel in a concentration-dependent manner. Our findings delineate the molecular architecture and function of hGluD1, provide foundations for understanding patient mutations in hGluD1, and will invigorate therapeutic development against hGluD1.
SN - 2752-6542
ER -