期刊
EMBO JOURNAL
卷 30, 期 5, 页码 972-982出版社
WILEY
DOI: 10.1038/emboj.2011.17
关键词
AMPA receptor allostery; AMPA receptor function; GluA3 N-terminal domain structure; NTD ligand
资金
- MRC
- NIH [5R01GM086238-02, U54GM087519]
- Royal Society
- Medical Research Council [MC_U105174197] Funding Source: researchfish
- MRC [MC_U105174197] Funding Source: UKRI
Glutamate-gated ion channels (ionotropic glutamate receptors, iGluRs) sense the extracellular milieu via an extensive extracellular portion, comprised of two clam-shell-shaped segments. The distal, N-terminal domain (NTD) has allosteric potential in NMDA-type iGluRs, which has not been ascribed to the analogous domain in AMPA receptors (AMPARs). In this study, we present new structural data uncovering dynamic properties of the GluA2 and GluA3 AMPAR NTDs. GluA3 features a zipped-open dimer interface with unconstrained lower clamshell lobes, reminiscent of metabotropic GluRs (mGluRs). The resulting labile interface supports interprotomer rotations, which can be transmitted to downstream receptor segments. Normal mode analysis reveals two dominant mechanisms of AMPAR NTD motion: intraprotomer clamshell motions and interprotomer counter-rotations, as well as accessible interconversion between AMPAR and mGluR conformations. In addition, we detect electron density for a potential ligand in the GluA2 interlobe cleft, which may trigger lobe motions. Together, these data support a dynamic role for the AMPAR NTDs, which widens the allosteric landscape of the receptor and could provide a novel target for ligand development. The EMBO Journal (2011) 30, 972-982. doi: 10.1038/emboj.2011.17; Published online 11 February 2011
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