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Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session V Abstracts
Dynamics and Function of the AMPA Receptor N-Terminal Domain
Ingo Greger
.
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the majority of
excitatory neurotransmission in the brain. AMPAR malfunction underlies a variety of
neurological disorders rendering them a central drug target. AMPARs consist of four core
subunits (GluAs) and a variety of auxiliary subunits that modulate receptor gating. The GluA
core comprises two layers at the extracellular face of the receptor – the membrane-proximal
ligand-binding domain (LBD) and the distal N-terminal domain (NTD), clamshell-shaped
structures belonging to the periplasmic-binding protein family. The NTD is the most sequence-
diverse portion and encompasses 50% of primary polypeptide sequence; the precise role of this
domain is nevertheless obscure.
Our work has highlighted NTD allosteric capacity, which appeared pronounced in the GluA3
subunit [1, 2]. We have solved numerous GluA3 NTD structures in an attempt to co-crystallize
small-molecule NTD modulators. This assemble of high-resolution structures reveal a spectrum
of NTD dimer assemblies giving rise to two dominant modes of motion: i) a shearing motion,
described by a rotation axis running through the upper lobe of the clamshell dimer-interface,
resulting in a 18 angstrom displacement of the clamshell lower lobes, and ii) an opening motion,
resulting in the splaying apart of the lower lobe dimer interface. These motions can be
recapitulated in coarse grain simulations using the anisotropic network model [1, 2] and in all-
atom molecular dynamics simulations further implying allosteric capacity for the NTD.
Moreover, we describe an unexpected interaction of the NTD with AMPAR auxiliary subunits.
We show that these proteins bridge the loosely connected NTD layer to the rest of the receptor,
creating a continuous allosteric path from the NTD to modulate channel activity.
References:
[1] Sukumaran et al., (2011).
EMBO J
. 30, p 972.
[2] Dutta et al., (2012).
Structure
20, p. 1838.
