Cryo-EM structure of phosphodiesterase 6 reveals insights into the allosteric regulation of type I phosphodiesterases

Sci Adv. 2019 Feb 27;5(2):eaav4322. doi: 10.1126/sciadv.aav4322. eCollection 2019 Feb.

Abstract

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 PDE6αβ2γ complex. The final density map resolved at 3.4 Å reveals several previously unseen structural features, including a coiled N-terminal domain and the interface of PDE6γ subunits with the PDE6αβ heterodimer. Comparison of the PDE6αβ2γ complex with the closed state of PDE2A sheds light on the conformational changes associated with the allosteric activation of type I PDEs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Animals
  • Cryoelectron Microscopy
  • Cyclic Nucleotide Phosphodiesterases, Type 1 / chemistry*
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / chemistry*
  • Models, Molecular*
  • Protein Conformation*
  • Protein Multimerization
  • Protein Subunits / chemistry

Substances

  • Protein Subunits
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Cyclic Nucleotide Phosphodiesterases, Type 6