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TitleStructural and functional dynamics of human cone cGMP-phosphodiesterase important for photopic vision.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 1, Page e2419732121, Year 2025
Publish dateJan 7, 2025
AuthorsSneha Singh / Dhiraj Srivastava / Kimberly Boyd / Nikolai O Artemyev /
PubMed AbstractCone cGMP-phosphodiesterase (PDE6) is the key effector enzyme for daylight vision, and its properties are critical for shaping distinct physiology of cone photoreceptors. We determined the structures ...Cone cGMP-phosphodiesterase (PDE6) is the key effector enzyme for daylight vision, and its properties are critical for shaping distinct physiology of cone photoreceptors. We determined the structures of human cone PDE6C in various liganded states by single-particle cryo-EM that reveal essential functional dynamics and adaptations of the enzyme. Our analysis exposed the dynamic nature of PDE6C association with its regulatory γ-subunit (Pγ) which allows openings of the catalytic pocket in the absence of phototransduction signaling, thereby controlling photoreceptor noise and sensitivity. We demonstrate evolutionarily recent adaptations of PDE6C stemming from residue substitutions in the Pγ subunit and the noncatalytic cGMP binding site and influencing the Pγ dynamics in holoPDE6C. Thus, our structural analysis sheds light on the previously unrecognized molecular evolution of the effector enzyme in cones that advances adaptation for photopic vision.
External linksProc Natl Acad Sci U S A / PubMed:39739818 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 4.1 Å
Structure data

EMDB-45989: Structure of PDE6C without inhibitory p gamma
Method: EM (single particle) / Resolution: 4.1 Å

45990

9cxg

EMDB-45990, PDB-9cxg:
Structure of PDE6C in complex with inhibitory cone p gamma in the presence of cGMP
Method: EM (single particle) / Resolution: 3.0 Å

45991

9cxh

EMDB-45991, PDB-9cxh:
Structure of PDE6C in complex with the rod inhibitory p gamma subunit in the presence of cGMP
Method: EM (single particle) / Resolution: 3.1 Å

45992

9cxi

EMDB-45992, PDB-9cxi:
Structure of PDE6C in complex with the rod inhibitory p gamma subunit in the absence of added cGMP
Method: EM (single particle) / Resolution: 3.0 Å

45993

9cxj

EMDB-45993, PDB-9cxj:
Structure of PDE6C in complex with the rod inhibitory p gamma subunit with disordered GafA region
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-PCG:
CYCLIC GUANOSINE MONOPHOSPHATE

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-5GP:
GUANOSINE-5'-MONOPHOSPHATE

Source
  • homo sapiens (human)
  • bos taurus (domestic cattle)
  • mus musculus (house mouse)
KeywordsHYDROLASE / PDE6C / PDE6-cGMP-GMP complex / PDE6C rod p gamma complex

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