Molecular lock regulates binding of glycine to a primitive NMDA receptor

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....

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-11, Vol.113 (44), p.E6786-E6795
Main Authors: Yu, Alvin, Alberstein, Robert, Thomas, Alecia, Zimmet, Austin, Grey, Richard, Mayer, Mark L., Lau, Albert Y.
Format: Article
Language:English
Subjects:
Amino acids
Animals
BASIC BIOLOGICAL SCIENCES
Binding Sites
Binding, Competitive
Biochemical analysis
Biological Sciences
Crystallography
Crystallography, X-Ray
Ctenophora - metabolism
Dipeptides
Electrophysiology
free energy calculations
glutamate receptors
Glycine - chemistry
Glycine - metabolism
Humans
Hydrogen Bonding
Ligands
Metazoa
Mnemiopsis leidyi
Models, Molecular
Molecular Dynamics Simulation
molecular dynamics simulations
Molecules
Mutant Proteins
Mutation
PNAS Plus
Point Mutation
Protein Binding - genetics
Protein Conformation
Receptors, Ionotropic Glutamate - metabolism
Receptors, N-Methyl-D-Aspartate - chemistry
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Vertebrates
X-ray crystallography
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1607010113