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Conformational spread and dynamics in allostery of NMDA receptors.


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.

SUBMITTER: Durham RJ 

PROVIDER: S-EPMC7035515 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Conformational spread and dynamics in allostery of NMDA receptors.

Durham Ryan J RJ   Paudyal Nabina N   Carrillo Elisa E   Bhatia Nidhi Kaur NK   Maclean David M DM   Berka Vladimir V   Dolino Drew M DM   Gorfe Alemayehu A AA   Jayaraman Vasanthi V  

Proceedings of the National Academy of Sciences of the United States of America 20200203 7


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  ...[more]

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