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



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



Structure 23(1): 228-236



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.

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Accession: 058715787

Download citation: RISBibTeXText

PMID: 25543253

DOI: 10.1016/j.str.2014.11.012


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