Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

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.

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