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Obtaining the open-pore conformation of the NMDA receptor


EMSL Project ID
51166

Abstract

NMDA receptors (NMDARs) are responsible for the fast-component of the excitatory neurotransmission in the central nervous system, along with AMPA receptors. These receptors have a unique and essential role in memory formation and for the development of neuronal long term potentiation and plasticity. Hyper-activation of NMDARs has been implicated in Alzheimer’s, Huntington’s, and Parkinson’s diseases, whereas hypoactivity is associated with depression, cognitive impairment, and schizophrenia. Understanding the molecular underpinnings of these receptors’ gating and activation is critical for the development of specific therapeutics aimed at positive or negative functional modulation. We plan to obtain the structure of the receptor in the open-gate conformation by using agonists alongside a combination of conditions such as zinc chelating reagents, cholesterol-like lipids, and high pH buffers, which we have shown to be favorable to receptor activation. We also plan on studying the open-pore conformation of the NMDARs by hyperactive mutants, a pharmacological positive allosteric modulator, as well as a class of pore blockers dubbed ‘foot-in-the-door’, as they are expected to lodge in the pore and stabilize the open conformation while blocking the ion-permeation pathway. Therefore, we have three main aims in this proposal:

Specific Aim 1: To obtain a high-resolution structure of the NMDA receptor in the open-pore conformation.
Specific Aim 2: To understand the molecular mechanism of “foot-in-the-door” block of NMDA receptors.
Specific Aim 3: To understand the mechanism of action of NMDAR positive allosteric modulators which binds at the trans-membrane domain.

Project Details

Start Date
2019-11-10
End Date
2021-03-17
Status
Closed

Team

Principal Investigator

Eric Gouaux
Institution
Oregon Health & Science University

Team Members

Prerana Gogoi
Institution
Oregon Health & Science University

Junhoe Kim
Institution
Oregon Health & Science University

Heidi Owen
Institution
Oregon Health & Science University

Vikas Navratna
Institution
Oregon Health & Science University

Farzad Jalali-Yazdi
Institution
Oregon Health & Science University

Janette Myers
Institution
Oregon Health & Science University