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Title: Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation

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:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [2] ;  [7]
  1. Baylor College of Medicine, Houston, TX (United States). Dept. of Pharmacology; Univ. of Kassel (Germany). Dept. of Biochemistry
  2. Univ. of Kassel (Germany). Dept. of Biochemistry
  3. King Abdullah Univ. of Science and Technology (KAUST), Thuwal (Saudi Arabia). Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering
  4. Baylor College of Medicine, Houston, TX (United States). Dept. of Pharmacology
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
  6. Univ. of California, San Diego, CA (United States). Dept. of Medicine
  7. Baylor College of Medicine, Houston, TX (United States). Dept. of Pharmacology; Baylor College of Medicine, Houston, TX (United States). Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology
Publication Date:
Grant/Contract Number:
AC02-05CH11231; R01 GM090161; R21 HL111953; 241481
Type:
Published Article
Journal Name:
Structure
Additional Journal Information:
Journal Volume: 24; Journal Issue: 5; Journal ID: ISSN 0969-2126
Publisher:
Elsevier
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); King Abdullah University of Science and Technology (KAUST); European Union (EU)
Country of Publication:
United States
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
OSTI Identifier:
1355066
Alternate Identifier(s):
OSTI ID: 1379328

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 States: N. p., 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 States. 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., and Kim, Choel. 2016. "Crystal Structure of PKG I:cGMP Complex Reveals a cGMP-Mediated Dimeric Interface that Facilitates cGMP-Induced Activation". United States. doi: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 States},
year = {2016},
month = {4}
}