Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation
Abstract
Cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) is a key regulator of smooth muscle and vascular tone and represents an important drug target for treating hypertensive diseases and erectile dysfunction. Despite its importance, its activation mechanism is not fully understood. To understand the activation mechanism, we determined a 2.5 Å crystal structure of the PKG I regulatory (R) domain bound with cGMP, which represents the activated state. Here, although we used a monomeric domain for crystallization, the structure reveals that two R domains form a symmetric dimer where the cGMP bound at high-affinity pockets provide critical dimeric contacts. Small-angle X-ray scattering and mutagenesis support this dimer model, suggesting that the dimer interface modulates kinase activation. Finally, structural comparison with the homologous cyclic AMP-dependent protein kinase reveals that PKG is drastically different from protein kinase A in its active conformation, suggesting a novel activation mechanism for PKG.
- Authors:
- 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); King Abdullah University of Science and Technology (KAUST); European Union (EU)
- OSTI Identifier:
- 1355066
- Alternate Identifier(s):
- OSTI ID: 1379328
- Grant/Contract Number:
- AC02-05CH11231; R01 GM090161; R21 HL111953; 241481
- Resource Type:
- Published Article
- Journal Name:
- Structure
- Additional Journal Information:
- Journal Name: Structure Journal Volume: 24 Journal Issue: 5; Journal ID: ISSN 0969-2126
- Publisher:
- Elsevier
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; NO-cGMP signaling; second messengers; cGMP-dependent protein kinase; cyclic nucleotide-binding domain; allosteric activation; crystal structure; small-angle X-ray scattering
Citation Formats
Kim, Jeong Joo, Lorenz, Robin, Arold, Stefan T., Reger, Albert S., Sankaran, Banumathi, Casteel, Darren E., Herberg, Friedrich W., and Kim, Choel. Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation. United Kingdom: N. p., 2016.
Web. doi:10.1016/j.str.2016.03.009.
Kim, Jeong Joo, Lorenz, Robin, Arold, Stefan T., Reger, Albert S., Sankaran, Banumathi, Casteel, Darren E., Herberg, Friedrich W., & Kim, Choel. Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation. United Kingdom. https://doi.org/10.1016/j.str.2016.03.009
Kim, Jeong Joo, Lorenz, Robin, Arold, Stefan T., Reger, Albert S., Sankaran, Banumathi, Casteel, Darren E., Herberg, Friedrich W., and Kim, Choel. Sun .
"Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation". United Kingdom. https://doi.org/10.1016/j.str.2016.03.009.
@article{osti_1355066,
title = {Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation},
author = {Kim, Jeong Joo and Lorenz, Robin and Arold, Stefan T. and Reger, Albert S. and Sankaran, Banumathi and Casteel, Darren E. and Herberg, Friedrich W. and Kim, Choel},
abstractNote = {Cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) is a key regulator of smooth muscle and vascular tone and represents an important drug target for treating hypertensive diseases and erectile dysfunction. Despite its importance, its activation mechanism is not fully understood. To understand the activation mechanism, we determined a 2.5 Å crystal structure of the PKG I regulatory (R) domain bound with cGMP, which represents the activated state. Here, although we used a monomeric domain for crystallization, the structure reveals that two R domains form a symmetric dimer where the cGMP bound at high-affinity pockets provide critical dimeric contacts. Small-angle X-ray scattering and mutagenesis support this dimer model, suggesting that the dimer interface modulates kinase activation. Finally, structural comparison with the homologous cyclic AMP-dependent protein kinase reveals that PKG is drastically different from protein kinase A in its active conformation, suggesting a novel activation mechanism for PKG.},
doi = {10.1016/j.str.2016.03.009},
journal = {Structure},
number = 5,
volume = 24,
place = {United Kingdom},
year = {Sun May 01 00:00:00 EDT 2016},
month = {Sun May 01 00:00:00 EDT 2016}
}
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https://doi.org/10.1016/j.str.2016.03.009
https://doi.org/10.1016/j.str.2016.03.009
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Cited by: 30 works
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Works referencing / citing this record:
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- Journal of Translational Medicine, Vol. 18, Issue 1
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