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

Science Advances
Sahil GulatiLubomir Kovacik

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.

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Citations

Aug 21, 2020·The Journal of Biological Chemistry·Annika N BoehmAnnette Aichem
Dec 22, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Wesam S AhmedKabir H Biswas
May 5, 2021·Current Opinion in Structural Biology·Sahil Gulati, Krzysztof Palczewski
Dec 22, 2021·ELife·Matthias PögeWolfgang Baumeister

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Datasets Mentioned

BETA
EMD-9297
EMPIAR-10228

Methods Mentioned

BETA
cross-linking studies

Software Mentioned

py
SerialEM
S3D
PSIPRED
Relion
Chimera
CTFFIND4
e2boxer
auto
cisTEM

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