Molecular lock regulates binding of glycine to a primitive NMDA receptor
Abstract
The earliest metazoan ancestors of humans include the ctenophore Mnemiopsis leidyi. Here, 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.
- Authors:
-
- Johns Hopkins Univ., Baltimore, MD (United States)
- Johns Hopkins Univ., Baltimore, MD (United States); National Inst. of Health (NIH), Bethesda, MD (United States); Univ. of California, San Diego, La Jolla, CA (United States)
- National Inst. of Health (NIH), Bethesda, MD (United States); Univ. of Maryland, Baltimore, MD (United States)
- National Inst. of Health (NIH), Bethesda, MD (United States); Univ. of Pennsylvania Perelman School of Medicine, Philadelphia, PA (United States)
- National Inst. of Health (NIH), Bethesda, MD (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
- OSTI Identifier:
- 1335988
- Grant/Contract Number:
- W-31-109-Eng-38; R01GM094495
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 113; Journal Issue: 44; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; glutamate receptors; X-ray crystallography; electrophysiology; molecular dynamics simulations; free energy calculations
Citation Formats
Yu, Alvin, Alberstein, Robert, Thomas, Alecia, Zimmet, Austin, Grey, Richard, Mayer, Mark L., and Lau, Albert Y. Molecular lock regulates binding of glycine to a primitive NMDA receptor. United States: N. p., 2016.
Web. doi:10.1073/pnas.1607010113.
Yu, Alvin, Alberstein, Robert, Thomas, Alecia, Zimmet, Austin, Grey, Richard, Mayer, Mark L., & Lau, Albert Y. Molecular lock regulates binding of glycine to a primitive NMDA receptor. United States. https://doi.org/10.1073/pnas.1607010113
Yu, Alvin, Alberstein, Robert, Thomas, Alecia, Zimmet, Austin, Grey, Richard, Mayer, Mark L., and Lau, Albert Y. Mon .
"Molecular lock regulates binding of glycine to a primitive NMDA receptor". United States. https://doi.org/10.1073/pnas.1607010113. https://www.osti.gov/servlets/purl/1335988.
@article{osti_1335988,
title = {Molecular lock regulates binding of glycine to a primitive NMDA receptor},
author = {Yu, Alvin and Alberstein, Robert and Thomas, Alecia and Zimmet, Austin and Grey, Richard and Mayer, Mark L. and Lau, Albert Y.},
abstractNote = {The earliest metazoan ancestors of humans include the ctenophore Mnemiopsis leidyi. Here, 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.},
doi = {10.1073/pnas.1607010113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 44,
volume = 113,
place = {United States},
year = {Mon Oct 17 00:00:00 EDT 2016},
month = {Mon Oct 17 00:00:00 EDT 2016}
}
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