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Structures of human PKG reveal cGMP-selectived activation mechanisms

Journal Article · · BMC Pharmacology & Toxicology
 [1];  [2];  [2];  [3];  [2];  [4];  [5];  [3];  [6];  [6];  [7];  [8];  [6];  [3];  [9]
  1. Baylor Univ., Houston, TX (United States). College of Medicine. Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology; DOE/OSTI
  2. Baylor Univ., Houston, TX (United States). College of Medicine. Dept. of Pharmacology
  3. Univ. of Kassel (Germany). Dept. of Biochemistry
  4. Rice Univ., Houston, TX (United States). Dept. of Chemistry
  5. Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Medicine
  6. McMaster Univ., Hamilton, ON (Canada). Dept. of Chemistry and Chemical Biology
  7. Rigaku Americas, The Woodlands, TX (United States)
  8. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
  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
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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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
OSTI ID:
1629600
Journal Information:
BMC Pharmacology & Toxicology, Journal Name: BMC Pharmacology & Toxicology Journal Issue: S1 Vol. 14; ISSN 2050-6511
Publisher:
BioMed CentralCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES