Biology Reference
In-Depth Information
exploiting this binding pose cause partial inhibition of activity. UCR2 capping of
one active site not only blocks catalysis at that site but also decreases the turnover
rate at the other active site. This explains why the maximum inhibition is
50%.
Such compounds are potent in cellular and in vivo assays, but have less effect on
cellular cAMP levels than do competitive PDE4 inhibitors. The intrinsic ceiling
on the magnitude of PDE4 inhibition may better maintain spatial and temporal
patterning of signaling in cAMP microdomains with the consequence that tolera-
bility is improved.
We showed that UCR2 capping affects cAMP hydrolysis as the Phe196/Tyr274
polymorphism affects apparent
K
M
(Burgin et al.
2010
). Given such insights, one
wonders whether endogenous ligands, other than cAMP, that modulate PDE4
activity in a cellular context exist. The gating mechanism for regulating PDE4
activity is probably general to other families of PDE as many of these contain
unique upstream regulatory domains (e.g., GAF domains in PDE2, 5, 6, 10, and 11;
Ca
2+/
calmodulin domains in PDE1; the PAS domain in PDE8) (Lugnier
2006
).
Pandit et al. have reported structures of the PDE2 catalytic domain with the GAF
regulatory domain (Pandit et al.
2009
). cGMP binding to the GAF domains induces
an allosteric shift in the PDE2 dimer interface that allows a regulatory helix to
uncap the active site, thereby allowing access of substrate. Sequence alignment of
PDE7 with PDE4 reveals homology across the UCR2 helix, inspection of the PDE7
catalytic domain (PDB ID: 3G3N) reveals a groove across the active site as in PDE4
suggestive of a capping site for a regulatory helix, and indeed, the PDE4 UCR2
regulatory helix can be docked into that groove
in silico
(Burgin, unpublished).
Thus, in PDE4, PDE2 and probably in PDE7, regulatory helices may control
enzymatic activity by gating access of substrate to the active site. PDE activity
may be fine tuned further by accessory proteins binding closed or open PDE
conformers.
>
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