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Dynamics and allosteric potential of the AMPA receptor N-terminal domain

DOI: 10.1038/emboj.2011.17 DOI Help
PMID: 21317871 PMID Help

Authors: Madhav Sukumaran (MRC Laboratory of Molecular Biology) , Maxim Rossmann (MRC Laboratory of Molecular Biology) , Indira Shrivastava (MRC Laboratory of Molecular Biology, Cambridge) , Anindita Dutta (MRC Laboratory of Molecular Biology, Cambridge) , Ivet Bahar (MRC Laboratory of Molecular Biology, Cambridge) , Ingo H. Greger (MRC Laboratory of Molecular Biology, Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal , VOL 30 (5) , PAGES 972-982

State: Published (Approved)
Published: March 2011
Diamond Proposal Number(s): 261

Abstract: Glutamate-gated ion channels (ionotropic glutamate receptors, iGluRs) sense the extracellular milieu via an extensive extracellular portion, comprised of two clamshell-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.

Journal Keywords: Amino; Calcium; Cell; Crystallography; X-Ray; Electrophysiology; Humans; Ion; Protein; Receptors; AMPA; Sequence; Amino; Ultracentrifugation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Added On: 29/03/2011 09:48

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)