Molecular lock regulates binding of glycine to a primitive NMDA receptor

作者：Yu Alvin; Alberstein Robert; Thomas Alecia; Zimmet Austin; Grey Richard; Mayer Mark L^*; Lau Albert Y^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(44): E6786-E6795.

DOI：10.1073/pnas.1607010113

• glutamate receptors
• X-ray crystallography
• electrophysiology
• molecular dynamics simulations
• free energy calculations

The earliest metazoan ancestors of humans include the ctenophore Mnemiopsis leidyi. The genome of this comb jelly encodes homologs of vertebrate ionotropic glutamate receptors (iGluRs) that are distantly related to glycine-activated NMDA receptors and that bind glycine with unusually high affinity. Using ligand-binding domain (LBD) mutants for electrophysiological analysis, we demonstrate that perturbing a ctenophore-specific interdomain Arg-Glu salt bridge that is notably absent from vertebrate AMPA, kainate, and NMDA iGluRs greatly increases the rate of recovery from desensitization, while biochemical analysis reveals a large decrease in affinity for glycine. X-ray crystallographic analysis details rearrangements in the binding pocket stemming from the mutations, and molecular dynamics simulations suggest that the interdomain salt bridge acts as a steric barrier regulating ligand binding and that the free energy required to access open conformations in the glycine-bound LBD is largely responsible for differences in ligand affinity among the LBD variants.

• 出版日期2016-11-1
• 单位NIH