107
Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session II
52-POS
Board 5
Co-evolutionary Analysis of Ionotropic Glutamate Receptor N-Terminal Domain Function
James Krieger
1
, Madhav Sukumaran
1
, Anindita Dutta
2
, Ivet Bahar
2
, Ingo Greger
1
.
1
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom,
2
University of
Pittsburgh, Pittsburgh, PA, USA.
Ionotropic glutamate receptors (iGluRs) are key mediators of synaptic transmission and
plasticity, especially those selective for alpha-amino-3-hydroxy-4-isoxazole propionic acid
(AMPA) and N-methyl-D-aspartate (NMDA). They are composed of a common domain
architecture with two extracellular periplasmic-binding protein (PBP)-like clamshell domains.
The membrane-proximal ligand-binding domain closes around agonists such as glutamate to pull
open the ion channel. The function of the distal N-terminal domain (NTD) is less clear though it
has been implicated in receptor assembly, synapse formation and allosteric modulation of
channel gating (at least for NMDA receptors). Here we have used various co-evolutionary
methods (statistical coupling analysis [SCA], direct coupling analysis [DCA] and mutual
information [MI]) to identify key residues and help elucidate the potential allosteric function of
this domain. Other receptors such as metabotropic glutamate receptors (mGluRs) and atrial
natriuretic peptide receptors (ANPRs) are known to use dimeric PBP-like domains as primary
ligand binding domains that allosterically transmit signals to the rest of the structure. As these
domains have similar sequences and structures to the iGluR NTD, these other receptors have
been included in the co-evolution analysis to gain further insights through commonalities and
differences. We believe that this PBP domain has evolved as useful scaffold for allostery and
there may be common input and output regions that are used to different extents in different
receptors. For example, mGluRs use the clamshell cleft of each protomer to bind glutamate and
induce inter-protomer conformational changes while the ANPRs primarily use the dimer
interface, which is also used by mGluRs to bind cations.
