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Molecular modeling annual

, Volume 6, Issue 1, pp 16–25 | Cite as

Structural Insights Into NMDA Ionotropic Glutamate Receptors via Molecular Modelling

  • Kamaldeep K. Chohan
  • Z. Galen Wo
  • Robert E. Oswald
  • Michael J. Sutcliffe
Full Paper

Abstract

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.

Keywords Agonist binding, Selectivity, Cation channel 

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Copyright information

© Springer-Verlag Heidelberg 2000

Authors and Affiliations

  • Kamaldeep K. Chohan
    • 1
  • Z. Galen Wo
    • 2
  • Robert E. Oswald
    • 2
  • Michael J. Sutcliffe
    • 1
  1. 1.Department of Chemistry, University of Leicester, Leicester, LE1 7RH, United Kingdom. Tel.: +44-116 252 3601; Fax: +44-116 252 3789. E-mail: sjm@le.ac.ukGB
  2. 2.Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USAUS

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