D-Serine Potently Drives Ligand-Binding Domain Closure in the Ionotropic Glutamate Receptor GluD2

• Published in: Structure (London) 2020-10, Vol.28 (10), p.1168-1178.e2
• Main Authors: Chin, Alfred C., Yovanno, Remy A., Wied, Tyler J., Gershman, Ariel, Lau, Albert Y.
• Format: Article
• Language: English
• Subjects: delta receptor; free energy calculations; glutamate receptors; GRID2 gene; ligand-gated receptors; molecular dynamics simulations
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2020.07.005

Despite their classification as ionotropic glutamate receptors, GluD receptors are not functional ligand-gated ion channels and do not bind glutamate. GluD2 receptors bind D-serine and coordinate transsynaptic complexes that regulate synaptic plasticity. Instead of opening the ion channel pore, mechanical tension produced from closure of GluD2 ligand-binding domains (LBDs) drives conformational rearrangements for non-ionotropic signaling. We report computed conformational free energy landscapes for the GluD2 LBD in apo and D-serine-bound states. Unexpectedly, the conformational free energy associated with GluD2 LBD closure upon D-serine binding is greater than that for AMPA, NMDA, and kainate receptor LBDs upon agonist binding. This excludes insufficient force generation as an explanation for lack of ion channel activity in GluD2 receptors and suggests that non-ionotropic conformational rearrangements do more work than pore opening. We also report free energy landscapes for GluD2 LBD harboring a neurodegenerative mutation and demonstrate selective stabilization of closed conformations in the apo state. [Display omitted] •D-serine binding to the GluD2 receptor strongly drives ligand-binding domain closure•A neurodegenerative mutation in GluD2 stabilizes activated states of the LBD•Ligand accessibility analysis quantifies LBD conformational thermodynamics The GluD family of ionotropic glutamate receptors (iGluRs) lacks functional ion channel activity. Surprisingly, computed conformational free energies reveal that agonist binding in GluD2 receptors drives ligand-binding domain (LBD) closure more strongly than observed in other iGluRs. A neurodegenerative mutation within the GluD2 LBD stabilizes closed, active conformations.