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ORIGINAL RESEARCH article

Front. Physiol.
Sec. Computational Physiology and Medicine
Volume 15 - 2024 | doi: 10.3389/fphys.2024.1446459

Structural prediction of GluN3 NMDA Receptors

Provisionally accepted
ZENGWEI Kou ZENGWEI Kou 1,2*Yunsheng Liu Yunsheng Liu 3Da Shao Da Shao 4Shulei Lou Shulei Lou 5
  • 1 University of Toronto, Toronto, Canada
  • 2 Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 3 Department of Neurology, Shenzhen Institute of Translational Medicine, Shenzhen Second People's Hospital, Shenzhen, Guangdong Province, China
  • 4 School of Medicine, Shanghai Jiao Tong University, Shanghai, Shanghai Municipality, China
  • 5 Linyi People's Hospital, Linyi, Shandong Province, China

The final, formatted version of the article will be published soon.

    NMDA receptors are heterotetrametric ion channels composed of two obligatory GluN1 subunits and two alternative GluN2 or GluN3 subunits, forming GluN1-N2, GluN1-N3, and GluN1-N2-N3 type of NMDA receptors. Extensive research has focused on the functional and structural properties of conventional GluN1-GluN2 NMDA receptors due to their early discovery and high expression levels. However, the knowledge of unconventional GluN1-N3 NMDA receptors remains limited. In this study, we modeled the GluN1-N3A, GluN1-N3B, and GluN1-N3A-N3A NMDA receptors using deep-learned protein-language predication algorithm AlphaFold and RoseTTAFold All-Atom. We then compared these structures with GluN1-N2 and GluN1-N3A receptor cryo-EM structures and found GluN1-N3 receptors have distinct properties in subunit arrangement, domain swap, and domain interaction. Furthermore, we predicted the agonist-or antagonist-bound structures, highlighting the key molecular-residue interactions. Our findings shed new light on the structural and functional diversity of NMDA receptors and provides new direction for drug development.

    Keywords: NMDA receptors, AlphaFold, RoseTTAFold, Protein prediction, ion channel, ligand receptors

    Received: 09 Jun 2024; Accepted: 29 Jul 2024.

    Copyright: © 2024 Kou, Liu, Shao and Lou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: ZENGWEI Kou, University of Toronto, Toronto, Canada

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.