Reduced curvature of ligand-binding domain free-energy surface underlies partial agonism at NMDA receptors

Structure. 2015 Jan 6;23(1):228-236. doi: 10.1016/j.str.2014.11.012. Epub 2014 Dec 24.


NMDA receptors are ligand-gated ion channels that mediate excitatory synaptic transmission in the central nervous system. Partial agonists elicit submaximal channel activation, but crystal structures of the ligand-binding domains (LBDs) bound with partial and full agonists show little difference. To uncover the molecular mechanism for partial agonism, here we computed the free-energy surfaces of the GluN1 (an obligatory subunit of NMDA receptors) LBD bound with a variety of ligands. The free-energy minima are similarly positioned for full and partial agonists, but the curvatures are significantly reduced in the latter case, indicating higher probabilities for sampling conformations with a not fully closed domain cleft. The free-energy surfaces for antagonists have both shifted minima and further reduced curvatures. Reduced curvature of free-energy surface appears to explain well the partial agonism at NMDA receptors and may present a unique paradigm in producing graded responses for receptors in general.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Drug Partial Agonism
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, N-Methyl-D-Aspartate / agonists*
  • Receptors, N-Methyl-D-Aspartate / chemistry*
  • Receptors, N-Methyl-D-Aspartate / metabolism*


  • Ligands
  • Receptors, N-Methyl-D-Aspartate