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Title: Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II

Journal Article · · Journal of Biological Chemistry
 [1];  [2];  [3];  [1];  [1];  [4];  [5];  [6];  [4];  [7];  [8];  [1]
  1. Baylor College of Medicine, Houston, TX (United States)
  2. Baylor College of Medicine, Houston, TX (United States); Univ. of Kassel, Hesse (Germany)
  3. Rice Univ., Houston, TX (United States)
  4. Univ. of Tokushima Graduate School (Japan)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  6. Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States)
  7. Baylor College of Medicine, Houston, TX (United States); Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States)
  8. Univ. of California, San Diego, CA (United States)
+ Show Author Affiliations

Membrane-bound cGMP-dependent protein kinase (PKG) II is an important regulator of bone growth, renin secretion, and memory formation. Despite its crucial physiological roles, little is known about its cyclic nucleotide selectivity mechanism due to a lack of structural information. Here, we find that the C-terminal cyclic nucleotide binding (CNB-B) domain of PKGII binds cGMP with higher affinity and selectivity when compared with its N-terminal CNB (CNB-A) domain. To understand the structural basis of cGMP selectivity, we solved co-crystal structures of the CNB domains with cyclic nucleotides. Our structures combined with mutagenesis demonstrate that the guanine-specific contacts at Asp-412 and Arg-415 of the αC-helix of CNB-B are crucial for cGMP selectivity and activation of PKG II. Structural comparison with the cGMP selective CNB domains of human PKG I and Plasmodium falciparum PKG (PfPKG) shows different contacts with the guanine moiety, revealing a unique cGMP selectivity mechanism for PKG II.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1379155
Journal Information:
Journal of Biological Chemistry, Vol. 291, Issue 11; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 16 works
Citation information provided by
Web of Science

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Cited By (3)

Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation. text January 2020
Active PKG II inhibited the growth and migration of ovarian cancer cells through blocking Raf/MEK and PI3K/Akt signaling pathways journal August 2019
Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation journal June 2019

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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY