期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 7, 页码 3839-3847出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1910950117
关键词
NMDA receptors; FRET; allostery; MD simulations
资金
- NIH [F31GM130035, K99NS094761, R01GM124233, R35GM122528]
- Houston Area Molecular Biophysics Training Program
- American Heart Association Postdoctoral Fellowship Program
- Training Interdisciplinary Pharmacology Scientists Program
- Cancer Prevention and Research Institute of Texas [DP150093]
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.
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