Molecular biology strives for the prediction of function, based on the genetic code. Within neuroscience, this is reflected in the intense study of the molecular basis for ligand recognition by neurotransmitter receptors. Consequently, structural and functional studies have rendered a profoundly high-resolution view of ionotropic glutamate receptors (iGluRs), the archetypal excitatory receptor in the brain. But even this view is obsolete: we don’t know why some receptors recognize glutamate yet others recognize other ligands; and we have been unable to functionally test the underlying chemical interactions. In other words, our view differs substantially from nature’s own view of ligand recognition. I plan to lead a workgroup attacking this problem on three fronts. First, bioinformatic identification and electrophysiological characterization of a broad and representative sample of iGluRs from across the spectrum of life will unveil the diversity of ligand recognition in iGluRs. Second, phylogenetic analyses combined with functional experiments will reveal the molecular changes that nature employed in arriving at existing means of ligand recognition in iGluRs. Finally, chemical-scale mutagenesis will be employed to overcome previous technical limitations and dissect the precise chemical interactions that determine the specific recognition of certain ligands. With my experience in combining phylogenetics and functional experiments and in the use of chemical-scale mutagenesis, the objectives are within reach. Together, they form a unique approach that will expose nature’s own view of ligand recognition in iGluRs, revealing the molecular blueprint for protein function in the nervous system.
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