Journal
SCIENCE ADVANCES
Volume 5, Issue 2, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aav4322
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Funding
- National Institutes of Health (NIH) [R24EY024864, R01EY027283]
- Research to Prevent Blindness (RPB)
- Canadian Institute for Advanced Research (CIFAR)
- Alcon Research Institute (ARI)
- Swiss Commission for Technology, and Innovation (CTI) [18272.1 PFLS-LS]
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Cyclic nucleotide phosphodiesterases (PDEs) work in conjunction with adenylate/guanylate cyclases to regulate the key second messengers of G protein-coupled receptor signaling. Previous attempts to determine the full-length structure of PDE family members at high-resolution have been hindered by structural flexibility, especially in their linker regions and N- and C-terminal ends. Therefore, most structure-activity relationship studies have so far focused on truncated and conserved catalytic domains rather than the regulatory domains that allosterically govern the activity of most PDEs. Here, we used single-particle cryo-electron microscopy to determine the structure of the full-length PDE6 alpha beta 2 gamma complex. The final density map resolved at 3.4 angstrom reveals several previously unseen structural features, including a coiled N-terminal domain and the interface of PDE6 gamma subunits with the PDE6 alpha beta heterodimer. Comparison of the PDE6 alpha beta 2 gamma complex with the closed state of PDE2A sheds light on the conformational changes associated with the allosteric activation of type I PDEs.
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