Structures of human PKG reveal cGMP-selectived activation mechanisms

Huang, Gilbert Y.; Kim, Jeong J.; Reger, Albert S.; Lorenz, Robin; Moon, Eui-Whan; Zhao, Chi; Casteel, Darren E.; Bertinetti, Daniela; VanSchouwen, Bryan; Selvaratnam, Rajeevan; Pflugrath, James W.; Sankaran, Banumathi; Melacini, Giuseppe; Herberg, Friedrich W.; Kim, Choel

doi:10.1186/2050-6511-14-s1-o16

Title: Structures of human PKG reveal cGMP-selectived activation mechanisms

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Abstract

Cyclic guanosine monophosphate (cGMP) is a key secondary messenger that is produced in response to nitric oxide. One of the key mediators of cGMP signaling, cGMPdependent protein kinase (PKG), is activated upon binding to cGMP and phosphorylates downstream substrates in a process required for important physiological processes such as vasodilation, nociception, and memory formation. PKGs are also known to mediate most effects of drugs that increase cellular cGMP levels, including nitric oxidereleasing agents and phosphodiesterase inhibitors, which are used for the treatment of angina pectoris and erectile dysfunction, respectively. It is known that PKG is preferentially activated by cGMP over cAMP roughly 60-100 fold – however, the molecular mechanism by which cGMP is distinguished from a structurally similar messenger, cAMP, is poorly defined. Using competition fluorescence polarization (FP), X-ray crystallography, and in vitro kinase assays, we sought to understand the molecular basis for cGMP selectivity in PKGI.

Authors:

Huang, Gilbert Y. ^[1]; Kim, Jeong J. ^[2]; Reger, Albert S. ^[2]; Lorenz, Robin ^[3]; Moon, Eui-Whan ^[2]; Zhao, Chi ^[4]; Casteel, Darren E. ^[5]; Bertinetti, Daniela ^[3]; VanSchouwen, Bryan ^[6]; Selvaratnam, Rajeevan ^[6]; Pflugrath, James W. ^[7]; Sankaran, Banumathi ^[8]; Melacini, Giuseppe ^[6]; Herberg, Friedrich W. ^[3]; Kim, Choel ^[9]

Baylor Univ., Houston, TX (United States). College of Medicine. Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology
Baylor Univ., Houston, TX (United States). College of Medicine. Dept. of Pharmacology
Univ. of Kassel (Germany). Dept. of Biochemistry
Rice Univ., Houston, TX (United States). Dept. of Chemistry
Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Medicine
McMaster Univ., Hamilton, ON (Canada). Dept. of Chemistry and Chemical Biology
Rigaku Americas, The Woodlands, TX (United States)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
Baylor Univ., Houston, TX (United States). College of Medicine. Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology; Baylor Univ., Houston, TX (United States). College of Medicine. Dept. of Pharmacology

Publication Date:: Thu Aug 29 00:00:00 EDT 2013

Research Org.:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

OSTI Identifier:: 1629600

Resource Type:: Accepted Manuscript

Journal Name:: BMC Pharmacology & Toxicology

Additional Journal Information:: Journal Volume: 14; Journal Issue: S1; Journal ID: ISSN 2050-6511

Publisher:: BioMed Central

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Huang, Gilbert Y., Kim, Jeong J., Reger, Albert S., Lorenz, Robin, Moon, Eui-Whan, Zhao, Chi, Casteel, Darren E., Bertinetti, Daniela, VanSchouwen, Bryan, Selvaratnam, Rajeevan, Pflugrath, James W., Sankaran, Banumathi, Melacini, Giuseppe, Herberg, Friedrich W., and Kim, Choel. Structures of human PKG reveal cGMP-selectived activation mechanisms.  United States: N. p., 2013. 
Web.  doi:10.1186/2050-6511-14-s1-o16.

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                    Huang, Gilbert Y., Kim, Jeong J., Reger, Albert S., Lorenz, Robin, Moon, Eui-Whan, Zhao, Chi, Casteel, Darren E., Bertinetti, Daniela, VanSchouwen, Bryan, Selvaratnam, Rajeevan, Pflugrath, James W., Sankaran, Banumathi, Melacini, Giuseppe, Herberg, Friedrich W., & Kim, Choel. Structures of human PKG reveal cGMP-selectived activation mechanisms.  United States.  https://doi.org/10.1186/2050-6511-14-s1-o16

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                    Huang, Gilbert Y., Kim, Jeong J., Reger, Albert S., Lorenz, Robin, Moon, Eui-Whan, Zhao, Chi, Casteel, Darren E., Bertinetti, Daniela, VanSchouwen, Bryan, Selvaratnam, Rajeevan, Pflugrath, James W., Sankaran, Banumathi, Melacini, Giuseppe, Herberg, Friedrich W., and Kim, Choel. Thu .  
"Structures of human PKG reveal cGMP-selectived activation mechanisms".  United States.  https://doi.org/10.1186/2050-6511-14-s1-o16.  https://www.osti.gov/servlets/purl/1629600.

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@article{osti_1629600,

  title        = {Structures of human PKG reveal cGMP-selectived activation mechanisms},

  author       = {Huang, Gilbert Y. and Kim, Jeong J. and Reger, Albert S. and Lorenz, Robin and Moon, Eui-Whan and Zhao, Chi and Casteel, Darren E. and Bertinetti, Daniela and VanSchouwen, Bryan and Selvaratnam, Rajeevan and Pflugrath, James W. and Sankaran, Banumathi and Melacini, Giuseppe and Herberg, Friedrich W. and Kim, Choel},

  abstractNote = {Cyclic guanosine monophosphate (cGMP) is a key secondary messenger that is produced in response to nitric oxide. One of the key mediators of cGMP signaling, cGMPdependent protein kinase (PKG), is activated upon binding to cGMP and phosphorylates downstream substrates in a process required for important physiological processes such as vasodilation, nociception, and memory formation. PKGs are also known to mediate most effects of drugs that increase cellular cGMP levels, including nitric oxidereleasing agents and phosphodiesterase inhibitors, which are used for the treatment of angina pectoris and erectile dysfunction, respectively. It is known that PKG is preferentially activated by cGMP over cAMP roughly 60-100 fold – however, the molecular mechanism by which cGMP is distinguished from a structurally similar messenger, cAMP, is poorly defined. Using competition fluorescence polarization (FP), X-ray crystallography, and in vitro kinase assays, we sought to understand the molecular basis for cGMP selectivity in PKGI.},

  doi          = {10.1186/2050-6511-14-s1-o16},

  journal      = {BMC Pharmacology & Toxicology},

  number       = S1,

  volume       = 14,

  place        = {United States},

  year         = {Thu Aug 29 00:00:00 EDT 2013},

  month        = {Thu Aug 29 00:00:00 EDT 2013}

}

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