The crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding

Kim, Jeong Joo; Casteel, Darren E.; Huang, Gilbert; Kwon, Taek Hun; Ren, Ronnie Kuo; Zwart, Peter; Headd, Jeffrey J.; Brown, Nicholas Gene; Chow, Dar-Chone; Palzkill, Timothy; Kim, Choel

doi:10.1186/1471-2210-11-S1-O14

Title: The crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding

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Abstract

Cyclic GMP is a crucial second messenger that translates extracellular signals into a variety of cellular responses. As a central mediator of the Nitric Oxide-cGMP signalling cascade, which regulates vascular tone, platelet aggregation, nociception and hipocampal/cerebellar learning, Cyclic GMP-dependent protein kinases (PKGs) represents an important drug target for treating hypertensive diseases and erectile dysfunction. The fidelity of the NO-cGMP signaling pathway is largely dependent on PKG’s ability to selectively bind cGMP over cAMP. Although both cGMP and cAMP bind and activate PKG, cGMP preferentially activates PKG 60-100 fold better than cAMP; yet, little is known about the molecular features required for the cGMP selectivity of PKG. We have investigated the mechanism of cyclic nucleotide binding to PKG by determining crystal structures of the amino-terminal cyclic nucleotide-binding domain (CNBD-A) of human PKG I bound to either cGMP or cAMP. We also determined the structure of CNBD-A in the absence of bound nucleotide.

Authors:

Kim, Jeong Joo ^[1]; Casteel, Darren E. ^[2]; Huang, Gilbert ^[3]; Kwon, Taek Hun ^[1]; Ren, Ronnie Kuo ^[4]; Zwart, Peter ^[5]; Headd, Jeffrey J. ^[5]; Brown, Nicholas Gene ^[3]; Chow, Dar-Chone ^[3]; Palzkill, Timothy ^[6]; Kim, Choel ^[7]

Baylor Univ., Houston, TX (United States). Dept. of Pharmacology
Univ. of California, San Diego, CA (United States). Dept. of Medicine
Baylor Univ., Houston, TX (United States). The Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology
Rice Univ., Houston, TX (United States)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). The Berkeley Center for structural Biology
Baylor Univ., Houston, TX (United States). Dept. of Pharmacology; Baylor Univ., Houston, TX (United States). The Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology; Baylor Univ., Houston, TX (United States). College of Medicine. Dept. of Molecular Virology and Microbiology
Baylor Univ., Houston, TX (United States). Dept. of Pharmacology; Baylor Univ., Houston, TX (United States). The Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology

Publication Date:: Mon Aug 01 00:00:00 EDT 2011

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:: 1629607

Grant/Contract Number:: AC02-05CH11231

Resource Type:: Accepted Manuscript

Journal Name:: BMC Pharmacology

Additional Journal Information:: Journal Volume: 11; Journal Issue: S1; Conference: 5. International Conference on cGMP: Generators, Effectors and Therapeutic Implications, Halle (Germany), 24-26 Jun 2011; Journal ID: ISSN 1471-2210

Publisher:: BioMed Central

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES

Citation Formats


                    Kim, Jeong Joo, Casteel, Darren E., Huang, Gilbert, Kwon, Taek Hun, Ren, Ronnie Kuo, Zwart, Peter, Headd, Jeffrey J., Brown, Nicholas Gene, Chow, Dar-Chone, Palzkill, Timothy, and Kim, Choel. The crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding.  United States: N. p., 2011. 
Web.  doi:10.1186/1471-2210-11-S1-O14.

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                    Kim, Jeong Joo, Casteel, Darren E., Huang, Gilbert, Kwon, Taek Hun, Ren, Ronnie Kuo, Zwart, Peter, Headd, Jeffrey J., Brown, Nicholas Gene, Chow, Dar-Chone, Palzkill, Timothy, & Kim, Choel. The crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding.  United States.  https://doi.org/10.1186/1471-2210-11-S1-O14

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                    Kim, Jeong Joo, Casteel, Darren E., Huang, Gilbert, Kwon, Taek Hun, Ren, Ronnie Kuo, Zwart, Peter, Headd, Jeffrey J., Brown, Nicholas Gene, Chow, Dar-Chone, Palzkill, Timothy, and Kim, Choel. Mon .  
"The crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding".  United States.  https://doi.org/10.1186/1471-2210-11-S1-O14.  https://www.osti.gov/servlets/purl/1629607.

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@article{osti_1629607,

  title        = {The crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding},

  author       = {Kim, Jeong Joo and Casteel, Darren E. and Huang, Gilbert and Kwon, Taek Hun and Ren, Ronnie Kuo and Zwart, Peter and Headd, Jeffrey J. and Brown, Nicholas Gene and Chow, Dar-Chone and Palzkill, Timothy and Kim, Choel},

  abstractNote = {Cyclic GMP is a crucial second messenger that translates extracellular signals into a variety of cellular responses. As a central mediator of the Nitric Oxide-cGMP signalling cascade, which regulates vascular tone, platelet aggregation, nociception and hipocampal/cerebellar learning, Cyclic GMP-dependent protein kinases (PKGs) represents an important drug target for treating hypertensive diseases and erectile dysfunction. The fidelity of the NO-cGMP signaling pathway is largely dependent on PKG’s ability to selectively bind cGMP over cAMP. Although both cGMP and cAMP bind and activate PKG, cGMP preferentially activates PKG 60-100 fold better than cAMP; yet, little is known about the molecular features required for the cGMP selectivity of PKG. We have investigated the mechanism of cyclic nucleotide binding to PKG by determining crystal structures of the amino-terminal cyclic nucleotide-binding domain (CNBD-A) of human PKG I bound to either cGMP or cAMP. We also determined the structure of CNBD-A in the absence of bound nucleotide.},

  doi          = {10.1186/1471-2210-11-S1-O14},

  journal      = {BMC Pharmacology},

  number       = S1,

  volume       = 11,

  place        = {United States},

  year         = {Mon Aug 01 00:00:00 EDT 2011},

  month        = {Mon Aug 01 00:00:00 EDT 2011}

}

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