Structural insights into NMDA ionotropic glutamate receptors via molecular modelling

Kamaldeep K. Chohan, Z. Galen Wo, Robert E. Oswald, Michael J. Sutcliffe

    Research output: Contribution to journalArticlepeer-review


    Structural models have been produced for the agonist binding and transmembrane domains of two NMDA ionotropic glutamate receptors: homomeric NMDA-R2C and heteromeric NMDA-R1/ R2C. These models - produced using homology modelling techniques in conjunction with distance restraints derived from the accessibility of substituted cysteines - have aided our understanding of (1) ligand selectivity and (2) channel activity. The model of the agonist binding domain of NMDA-R2C indicates that T691 forms an essential hydrogen bond with glutamate ligand. This interaction is absent in the NMDA-R1 model - where a valine replaces the threonine - explaining why NMDA-R1 binds glycine rather than glutamate. For the transmembrane region, the models suggest that a number of positive residues, located in the cytoplasmic loop between the M1 and M2 segments, create a large electrostatic energy barrier that could explain why homomeric NMDA-R2C channels are non-functional. Introducing NMDA-R1 to form heteromeric NMDA-R1/R2C channels is predicted to rescue channel activity because the corresponding region in NMDA-R1 contains negative residues that more than compensate for the electrostatic energy barrier in NMDA-R2C. These studies suggest that replacing the positively charged region in the M1-M2 loop of NMDA-R2C with the corresponding negatively charged region of NMDA-R1 could transform NMDA-R2C into a functional homomeric channel. © Springer-Verlag 2000.
    Original languageEnglish
    Pages (from-to)16-25
    Number of pages9
    JournalJournal of molecular modeling
    Issue number1
    Publication statusPublished - 2000


    • Agonist binding
    • Cation channel
    • Selectivity


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