Abstract
N-methyl-D-aspartate (NMDA) receptors belong to a family of ionotropic glutamate receptors that contribute to the signal transmission in the central nervous system. NMDA receptors are heterotetramers that usually consist of two GluN1 and GluN2 monomers. The extracellular ligand-binding domain (LBD) of a monomer is comprised of discontinuous segments that form the functional domains D1 and D2. While the binding of a full agonist glycine to LBD of GluN1 is linked to cleft closure and subsequent ion-channel opening, partial agonists are known to activate the receptor only sub-maximally. Although the crystal structures of the LBD of related GluA2 receptor explain the mechanism for the partial agonism, structures of GluN1-LBD cannot distinguish the difference between full and partial agonists. It is, however, probable that the partial agonists of GluN1 alter the structure of the LBD in order to result in a different pharmacological response than seen with full agonists. In this study, we used molecular dynamics simulations to reveal an intermediate closure-stage for GluN1, which is unseen in crystal structures. According to our calculations, this intermediate closure is not a transient stage but an energetically stable conformation. Our results demonstrate that the partial agonist cannot exert firm GluN1-LBD closure, especially if there is even a small force that disrupts the LBD closure. Accordingly, this result suggests the importance of forces from the ion channel for the relationship between pharmacological response and the structure of the LBD of members of this receptor family.
Highlights
N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors that contribute to signal transmission in the central nervous system [1]
We have previously shown that full agonists keep the iGluRLBD closed, whereas partial agonists destabilize the cleft closure [36]
To examine ligandbinding domain (LBD) closure in detail, we measured the distances between various atoms from molecular dynamics (MD) and steered molecular dynamics (SMD) trajectories to investigate the interactions that take place between the ligand and GluN1 during the closure of the GluN1 ligand-binding cleft
Summary
N-methyl-D-aspartate receptors (NMDARs) belong to a family of ionotropic glutamate receptors (iGluRs) that contribute to signal transmission in the central nervous system [1]. In the same study, GluN2-LBD exhibited an intermediate cleft closure when bound to a partial agonist. We performed steered molecular dynamics (SMD) simulations to study the firmness of full or partial agonist bound GluN1 structures.
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