Year of Award

2026

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Pharmaceutical Sciences and Drug Design

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Kasper B. Hansen

Commitee Members

Andrew R. Rau, Travis S. Hughes, Philippe Diaz, Bruce E. Bowler

Abstract

N-methyl-D-aspartate (NMDA) receptors are heterotetrameric ionotropic glutamate receptors widely expressed throughout the central nervous system where they mediate excitatory neurotransmission and serve as a molecular basis for learning and memory. Dysregulation of NMDA receptor activity has been implicated in a broad spectrum of neurological and psychiatric disorders including depression, schizophrenia, epilepsy, and neurodegenerative diseases. NMDA receptors assemble from GluN1, GluN2A-D, and GluN3AB subunits, producing substantial diversity in receptor pharmacology, kinetics, and function across brain regions and developmental stages. Despite this diversity, currently approved NMDA receptor modulators lack meaningful subtype selectivity, limiting their therapeutic utility and tolerability.

This dissertation investigates the structural and pharmacological basis for subtypespecific modulation of NMDA receptors across both conventional GluN2-containing and non-canonical GluN3-containing receptor classes. For conventional receptors, we show that subtype-specific glycine-site agonists displace helix F at the GluN1 agonist-binding domain, impairing a rolling conformational change at the interdimer interface that is required for full activation of GluN2B- and GluN2D-containing receptors but not GluN2A- or GluN2Ccontaining receptors. This catch and roll mechanism provides a structural explanation for how ligands binding at a conserved site on GluN1 can produce dramatically different functional outcomes depending on GluN2 subunit identity. For non-canonical receptors, we characterize UCM-A86 as the first positive allosteric modulator selective for GluN1/GluN3 over GluN1/GluN2 receptors, and use cryo-EM-guided mutagenesis and disulfide crosslinking to define structural determinants of the rapid and profound desensitization characteristic of GluN1/GluN3A receptors. Together, these studies advance understanding of how NMDA receptor subtype diversity arises from distinct conformational mechanisms and provide a structural framework for the rational development of subtype-selective therapeutics.

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