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Structural basis of cyclic nucleotide selectivity in cGMP-dependent Protein Kinase II

  • Author(s): Campbell, JC
  • Kim, JJ
  • Li, KY
  • Huang, GY
  • Reger, AS
  • Matsuda, S
  • Sankaran, B
  • Link, TM
  • Yuasa, K
  • Ladbury, JE
  • Casteel, DE
  • Kim, C
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786703/
No data is associated with this publication.
Abstract

© 2016, American Society for Biochemistry and Molecular Biology Inc. All rights reserved. Membrane-bound cGMP-dependent protein kinase (PKG) II is a key 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.

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