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Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time
Published on: March 11, 2021
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Discrimination between cyclic nucleotides in a cyclic nucleotide-gated ion channel
Yangang Pan1, Emmi Pohjolainen2, Philipp A M Schmidpeter1
1Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA.
Nature Structural & Molecular Biology
|March 27, 2023
Summary
Cyclic nucleotide-gated ion channels use cyclic adenosine monophosphate (cAMP) but not cyclic guanosine monophosphate (cGMP) for activation. This study reveals how SthK channel’s cyclic nucleotide binding domains (CNBDs) achieve this discrimination at the atomic level.
Area of Science:
- Biophysics
- Molecular Biology
- Structural Biology
Background:
- Cyclic nucleotide-gated (CNG) ion channels are vital for physiological processes like vision and cardiac pacemaking.
- SthK, a prokaryotic channel, shares structural and sequence similarities with eukaryotic CNG channels, particularly in cyclic nucleotide binding domains (CNBDs).
Purpose of the Study:
- To elucidate the atomic-level mechanism by which SthK CNBDs differentiate between cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).
- To understand the basis of cAMP-dependent activation versus minimal pore opening by cGMP.
Main Methods:
- Atomic force microscopy (AFM) single-molecule force spectroscopy.
- Force probe molecular dynamics (FPMD) simulations.
Main Results:
- cAMP binds to the SthK CNBD with slightly higher affinity than cGMP.
- cAMP can access a deep-bound state within the CNBD, which is inaccessible to cGMP.
- This deep-bound state of cAMP is proposed as the key discriminatory feature for channel activation.
Conclusions:
- The SthK CNBD exhibits differential binding affinities and conformational states for cAMP and cGMP.
- The ability of cAMP to reach a deep-bound state is critical for activating the SthK channel.
- This provides a molecular understanding of cyclic nucleotide discrimination in CNG channels.
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