Understanding the role of structure and dynamics in the functioning of ion channels
Ion channels have evolved to undergo rapid conformational changes in response to stimuli and thereby tightly regulate ionic fluxes and thus the cell physiology. They have varied architecture and broadly differ in the nature of stimuli, activation timescales and ionic selectivity. This structural and functional diversity allows them to critically govern the rate, duration and amount of current and as a result impact a multitude of cellular processes. One of the fundamental challenges in this field is to understand how spatially-separated structural motifs of the channel communicate in order to fine-tune its function. The primary focus of our research is to elucidate the conformational dynamics underlying allosteric mechanisms in ligand- and voltage-gated channels, and to determine how these processes control the basic features of channel function namely, gating and selectivity. We use a multidisciplinary approach which combines reporter-group spectroscopic techniques (site-directed spin labeling/EPR), electrophysiological methods (single-channel and macroscopic current measurements and model-based kinetic analysis), X-ray crystallography, and Cryo-EM along with classical biochemical and molecular biological procedures. These techniques complement each other and allow, at unprecedented detail, an atomic level description of how structure and dynamics govern protein functioning.
- Basak, S. a, Schmandt, N. a, Gicheru, Y a., and Chakrapani, S*. (2017) Crystal Structure of a Lipid-induced Desensitized State of a Pentameric Ligand-gated Channel (eLIFE, doi: 10.7554/eLife.23886).
- Schmandt, N., Velisetty, P., Chalamalasetti, S. V., Stein, R. A., Bonner, R., Talley, L., Parker, M. D., Mchaourab, H. S., Yee, V. C., Lodowski, D. T., and Chakrapani, S. (2015) An ELIC-GLIC Chimera Reveals Distinct Pathways of Activation in the Cys-loop receptors. J Gen Physiol, Oct;146(4):323-40. PMCID:PMC4586589
- Ostmeyer J, S Chakrapani, AC Pan, E Perozo & B Roux. Recovery from slow inactivation in K+ channels is controlled by water molecules. Nature 501:121-4, 2013.
- Velisetty P, SV Chalamalasetti & S Chakrapani. Conformational transitions underlying pore opening and desensitization in membrane-embedded Gloeobacter violaceus ligand-gated ion channel (GLIC). J. Biol. Chem. 287:36864-72, 2012.
- Velisetty P & S Chakrapani. Desensitization mechanism in prokaryotic ligand-gated ion channel. J. Biol. Chem. 287:18467-77, 2012.
- Chakrapani S, JF Cordero-Morales, V Jogini, AC Pan, DM Cortes, B Roux & E Perozo. On the structural basis of modal gating behavior in K(+) channels. Nat. Struct. Mol. Biol. 18:67-74, 2011.