Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2020 Feb 18;117(7):3839-3847. doi: 10.1073/pnas.1910950117. Epub 2020 Feb 3.

Conformational spread and dynamics in allostery of NMDA receptors.

Author information

1
Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030.
2
MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX 77030.
3
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642.
4
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030.
5
Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Houston, TX 77030; vasanthi.jayaraman@uth.tmc.edu.

Abstract

Allostery can be manifested as a combination of repression and activation in multidomain proteins allowing for fine tuning of regulatory mechanisms. Here we have used single molecule fluorescence resonance energy transfer (smFRET) and molecular dynamics simulations to study the mechanism of allostery underlying negative cooperativity between the two agonists glutamate and glycine in the NMDA receptor. These data show that binding of one agonist leads to conformational flexibility and an increase in conformational spread at the second agonist site. Mutational and cross-linking studies show that the dimer-dimer interface at the agonist-binding domain mediates the allostery underlying the negative cooperativity. smFRET on the transmembrane segments shows that they are tightly coupled in the unliganded and single agonist-bound form and only upon binding both agonists the transmembrane domain explores looser packing which would facilitate activation.

KEYWORDS:

FRET; MD simulations; NMDA receptors; allostery

PMID:
32015122
PMCID:
PMC7035515
[Available on 2020-08-03]
DOI:
10.1073/pnas.1910950117

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center