Journal
STRUCTURE
Volume 24, Issue 5, Pages 710-720Publisher
CELL PRESS
DOI: 10.1016/j.str.2016.03.009
Keywords
-
Funding
- NIH [R01 GM090161, R21 HL111953]
- NCI [Y1-CO-1020]
- NIGMS [Y1-GM-1104]
- CCP4
- STFC in the UK
- King Abdullah University of Science and Technology (KAUST)
- Federal Ministry of Education and Research Project NO PAIN [FKZ 0316177F]
- European Union (EU) FP7 collaborative project AFFINOMICS [241481]
- National Institute of General Medical Sciences
- Howard Hughes Medical Institute
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
- US DOE program Integrated Diffraction Analysis Technologies (IDAT)
- NIH project MINOS [R01 GM105404]
Ask authors/readers for more resources
Cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) is a key regulator of smooth muscle and vascular tone and represents an important drug target for treating hypertensive diseases and erectile dysfunction. Despite its importance, its activation mechanism is not fully understood. To understand the activation mechanism, we determined a 2.5 angstrom crystal structure of the PKG I regulatory (R) domain bound with cGMP, which represents the activated state. Although we used a monomeric domain for crystallization, the structure reveals that two R domains form a symmetric dimer where the cGMP bound at high-affinity pockets provide critical dimeric contacts. Small-angle X-ray scattering and mutagenesis support this dimer model, suggesting that the dimer interface modulates kinase activation. Finally, structural comparison with the homologous cyclic AMP-dependent protein kinase reveals that PKG is drastically different from protein kinase A in its active conformation, suggesting a novel activation mechanism for PKG.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available