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Publications of the Week

Allosteric Conformational Change of a Cyclic Nucleotide-Gated Ion Channel Revealed by DEER Spectroscopy

By May 14, 2020No Comments

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This week we profile a recent publication in PNAS from Dr. Eric Evans (pictured) in the laboratory
of Dr. Stefan Stoll, in collaboration with the laboratory of Dr. William Zagotta, at UW.

Can you provide a brief overview of your lab’s current research focus?

We are interested in a family of ion channel proteins that play critical roles in vision, olfaction, and the regulation of the heartbeat.  These channels open in response to chemical signals produced in response to light, odorant, or adrenaline—and convert this chemical signal into an electrical response.  We are interested in the molecular basis of this “chemo-electrical” coupling.  One of our primary tools is a magnetic resonance technique called DEER (double electron-electron resonance) spectroscopy, which can measure nanometer-scale distances between specific sites in the protein’s 3-D structure.  By analyzing how these distances change in response to stimuli, we can determine the conformational changes the protein undergoes during its physiological function, and better understand how this function is impaired in disease.   

What is the significance of the findings in this publication?

Using DEER in combination with electrophysiology, we were able to reveal a conformational change in a cyclic nucleotide-gated ion channel that we believe couples the binding of the activating ligand to the opening of the channel pore.  These results provide new insight into the structural mechanism of chemo-electrical coupling in this channel family.

What are the next steps for this research?

A fundamental question that remains unanswered is how the conformational change that we have observed here ultimately causes the channel to open.  DEER and other magnetic resonance techniques with different labeling strategies, combined with orthogonal structural techniques like cryo-electron microscopy, are likely to provide the answer.  We are also currently testing specific interactions in the channel that our molecular models suggest are important in stabilizing the active conformation.

This work was funded by:

NIH grants R01-EY010329, R01-GM127325, T32-EY007031, and T32-HL007312

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