Structure, Dynamics, and Allosteric Potential of Ionotropic Glutamate Receptor N-Terminal Domains

TL;DR

This paper explores the structure and function of the N-terminal domain in ionotropic glutamate receptors, focusing on its role in allosteric regulation and potential for drug development.

Contribution

The study provides new insights into the allosteric potential of the N-terminal domain in AMPA-type and NMDA-type ionotropic glutamate receptors using coarse-grained simulations.

Findings

The N-terminal domain's clamshell motions are coupled to rearrangements affecting the ligand-binding and transmembrane domains.

Allosteric regulation in the N-terminal domain impacts receptor function in synaptic environments.

The bilobate fold of the N-terminal domain is intrinsically linked to allostery in ionotropic glutamate receptors.

Abstract

Ionotropic glutamate receptors (iGluRs) are tetrameric cation channels that mediate synaptic transmission and plasticity. They have a unique modular architecture with four domains: the intracellular C-terminal domain (CTD) that is involved in synaptic targeting, the transmembrane domain (TMD) that forms the ion channel, the membrane-proximal ligand-binding domain (LBD) that binds agonists such as L-glutamate, and the distal N-terminal domain (NTD), whose function is the least clear. The extracellular portion, comprised of the LBD and NTD, is loosely arranged, mediating complex allosteric regulation and providing a rich target for drug development. Here, we briefly review recent work on iGluR NTD structure and dynamics, and further explore the allosteric potential for the NTD in AMPA-type iGluRs using coarse-grained simulations. We also investigate mechanisms underlying the established NTD allostery in NMDA-type iGluRs, as well as the fold-related metabotropic glutamate and GABAB receptors. We show that the clamshell motions intrinsically favored by the NTD bilobate fold are coupled to dimeric and higher-order rearrangements that impact the iGluR LBD and ultimately the TMD. Finally, we explore the dynamics of intact iGluRs and describe how it might affect receptor operation in a synaptic environment.

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