User:Rick H. Cote/PDE6

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PDE6: central effector of visual excitation in retinal rod and cone photoreceptors

Rod and cone photoreceptors of the vertebrate retina utilize cyclic nucleotides as the primary intracellular messenger for converting photic stimuli into an electrical response. Cyclic nucleotide levels in a dark-adapted photoreceptor are maintained by the balance of cyclic nucleotide synthesis (catalyzed by cyclases) and degradation (catalyzed by phosphodiesterases, PDEs). Upon light stimulation, the rapid activation of the photoreceptor PDE, classified as PDE6, triggers a dramatic drop in cyclic nucleotide levels that lead to cell hyperpolarization. The lifetime of activated PDE6 is also a highly regulated process. PDE6 inactivation is temporally coordinated with activation of the photoreceptor cyclase so that cyclic nucleotide levels recover quickly to restore the dark-adapted state of the photoreceptor.

Structure of PDE6 holoenzyme

PDE6 is a member of the Class I cyclic nucleotide phosphodiesterases, of which 11 families exist in mammals. Rod photoreceptor PDE6 holoenzyme consists of a catalytic heterodimer (PDE6A and PDE6B) to which two identical inhibitory gamma subunits (PDE6G) bind, forming a tetrameric complex. Cone PDE6 holoenzyme is a catalytic homodimer (2 identical PDE6C subunits) to which cone-specific gamma-subunits (PDE6H) bind.

  • 6MZB -- cryo-EM structure of rod PDE6 holoenzyme at 3.4 A resolution.

    Rod PDE6 holoenzyme, from Gulati et al., 2019

    PDE6 catalytic subunit partial structures

    • 3dba -- Crystal structure of the cGMP-bound GAF a domain from the photoreceptor phosphodiesterase 6C

      GAFa domain of PDE6C with bound cGMP

      PDE5/PDE6 chimeric structures

      • 3jwq -- Crystal structure of chimeric PDE5/PDE6 catalytic domain complexed with sildenafil
      • 3jwr -- Crystal structure of chimeric PDE5/PDE6 catalytic domain complexed with 3-isobutyl-1-methylxanthine (IBMX) and PDE6 gamma-subunit inhibitory peptide 70-87

      PDE6 inhibitory γ-subunit structures

      • 2ju4 -- NMR structure of the gamma subunit of cGMP phosphodiesterase
      • 1fqj -- CRYSTAL STRUCTURE OF THE HETEROTRIMERIC COMPLEX OF THE RGS DOMAIN OF RGS9, THE GAMMA SUBUNIT OF PHOSPHODIESTERASE AND THE GT/I1 CHIMERA ALPHA SUBUNIT [(RGS9)-(PDEGAMMA)-(GT/I1ALPHA)-(GDP)-(ALF4-)-(MG2+)]

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      Rick H. Cote

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