Synapses are able to modify their synaptic strength, this is typically achieved by regulating numbers and conductance of ion channels. This regulation is named synaptic plasticity and is important for long term learning and memory; problems in regulation cause a wide range of common neurodegenerative diseases. Our group aims at mechanistic understanding of ionotropic glutamate receptor gating using cryo-EM as a main tool.
Recent developments in cryo electron microscopy allow approaching problems that was difficult to solve with the other structural biology methods. In particular, it is now possible to understand structure of non-crystalline ion channels in atomic details at a resolution of 3-4 angstrom (http://www.ncbi.nlm.nih.gov/pubmed/25910205). This allows mechanistic understanding of gating and opens eventual opportunities for rational drug design. Our lab targets ionotropic glutamate receptors which are complex ion channels in the human brain implicated in numerous neurodegenerative diseases like depression and schizophrenia. They have modular architecture, are differentially expressed in different parts of the brain and regulate ion flow to the postsynaptic neuron. We use single particle cryo-EM to gain insights into gating and regulation of these important molecules. Even more exciting, now it is possible to study structure of membrane proteins at high resolution in membranes which Is critical for maintaining native conformations and functionality. For this we use sub-tomogam averaging from cryo electron tomograms (http://www.ncbi.nlm.nih.gov/pubmed/23466038), this allows observing ion channels at a resolution of secondary structure and may be combined with induction of the defined functional states. This "in situ" structural biology approach still requires developments in hardware and software. In our group we develop algorithms for sub-tomogram averaging at higher resolution using the entire range of modern tools. The developments are based on our Matab-based package Dynamo, and are actively shared with the EM community.