Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation
Abstract
The R‐diastereomer of phosphorothioate analogs of cGMP , Rp‐ cGMPS , is one of few known inhibitors of cGMP ‐dependent protein kinase I ( PKG I); however, its mechanism of inhibition is currently not fully understood. Here, we determined the crystal structure of the PKG Iβ cyclic nucleotide‐binding domain ( PKG Iβ CNB ‐B), considered a ‘gatekeeper’ for cGMP activation, bound to Rp‐ cGMPS at 1.3 Å. Our structural and NMR data show that PKG Iβ CNB ‐B bound to Rp‐ cGMPS displays an apo‐like structure with its helical domain in an open conformation. Comparison with the cAMP ‐dependent protein kinase regulatory subunit ( PKA RI α) showed that this conformation resembles the catalytic subunit‐bound inhibited state of PKA RI α more closely than the apo or Rp‐ cAMPS ‐bound conformations. These results suggest that Rp‐ cGMPS inhibits PKG I by stabilizing the inactive conformation of CNB‐B.
- Authors:
-
- Baylor College of Medicine, Houston, TX (United States). Structural and Computational Biology and Molecular Biophysics Program, Dept. of Chemistry and Chemical Biology
- McMaster Univ., Hamilton, ON (Canada). Dept. of Chemistry and Chemical Biology
- Univ. of Kassel, Hesse (Germany). Dept. of Biochemistry
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
- Baylor College of Medicine, Houston, TX (United States). Structural and Computational Biology and Molecular Biophysics Program, Dept. of Chemistry and Chemical Biology, Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
- OSTI Identifier:
- 1415962
- Alternate Identifier(s):
- OSTI ID: 1399282
- Grant/Contract Number:
- AC02-05CH11231; DE‐AC02‐05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- FEBS Letters
- Additional Journal Information:
- Journal Volume: 591; Journal Issue: 1; Journal ID: ISSN 0014-5793
- Publisher:
- Federation of European Biochemical Societies
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; cGMP dependent protein kinase; PKG; second messengers; NO-cGMP signaling; kinase inhibition
Citation Formats
Campbell, James C., VanSchouwen, Bryan, Lorenz, Robin, Sankaran, Banumathi, Herberg, Friedrich W., Melacini, Giuseppe, and Kim, Choel. Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation. United States: N. p., 2016.
Web. doi:10.1002/1873-3468.12505.
Campbell, James C., VanSchouwen, Bryan, Lorenz, Robin, Sankaran, Banumathi, Herberg, Friedrich W., Melacini, Giuseppe, & Kim, Choel. Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation. United States. https://doi.org/10.1002/1873-3468.12505
Campbell, James C., VanSchouwen, Bryan, Lorenz, Robin, Sankaran, Banumathi, Herberg, Friedrich W., Melacini, Giuseppe, and Kim, Choel. Fri .
"Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation". United States. https://doi.org/10.1002/1873-3468.12505. https://www.osti.gov/servlets/purl/1415962.
@article{osti_1415962,
title = {Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation},
author = {Campbell, James C. and VanSchouwen, Bryan and Lorenz, Robin and Sankaran, Banumathi and Herberg, Friedrich W. and Melacini, Giuseppe and Kim, Choel},
abstractNote = {The R‐diastereomer of phosphorothioate analogs of cGMP , Rp‐ cGMPS , is one of few known inhibitors of cGMP ‐dependent protein kinase I ( PKG I); however, its mechanism of inhibition is currently not fully understood. Here, we determined the crystal structure of the PKG Iβ cyclic nucleotide‐binding domain ( PKG Iβ CNB ‐B), considered a ‘gatekeeper’ for cGMP activation, bound to Rp‐ cGMPS at 1.3 Å. Our structural and NMR data show that PKG Iβ CNB ‐B bound to Rp‐ cGMPS displays an apo‐like structure with its helical domain in an open conformation. Comparison with the cAMP ‐dependent protein kinase regulatory subunit ( PKA RI α) showed that this conformation resembles the catalytic subunit‐bound inhibited state of PKA RI α more closely than the apo or Rp‐ cAMPS ‐bound conformations. These results suggest that Rp‐ cGMPS inhibits PKG I by stabilizing the inactive conformation of CNB‐B.},
doi = {10.1002/1873-3468.12505},
journal = {FEBS Letters},
number = 1,
volume = 591,
place = {United States},
year = {Fri Dec 23 00:00:00 EST 2016},
month = {Fri Dec 23 00:00:00 EST 2016}
}
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