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PDBsum entry 3jwr
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References listed in PDB file
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Key reference
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Title
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Structural basis of phosphodiesterase 6 inhibition by the c-Terminal region of the gamma-Subunit.
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Authors
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B.Barren,
L.Gakhar,
H.Muradov,
K.K.Boyd,
S.Ramaswamy,
N.O.Artemyev.
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Ref.
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Embo J, 2009,
28,
3613-3622.
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PubMed id
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Abstract
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The inhibitory interaction of phosphodiesterase-6 (PDE6) with its gamma-subunit
(Pgamma) is pivotal in vertebrate phototransduction. Here, crystal structures of
a chimaeric PDE5/PDE6 catalytic domain (PDE5/6cd) complexed with sildenafil or
3-isobutyl-1-methylxanthine and the Pgamma-inhibitory peptide Pgamma(70-87) have
been determined at 2.9 and 3.0 A, respectively. These structures show the
determinants and the mechanism of the PDE6 inhibition by Pgamma and suggest the
conformational change of Pgamma on transducin activation. Two variable H- and
M-loops of PDE5/6cd form a distinct interface that contributes to the
Pgamma-binding site. This allows the Pgamma C-terminus to fit into the opening
of the catalytic pocket, blocking cGMP access to the active site. Our analysis
suggests that disruption of the H-M loop interface and Pgamma-binding site is a
molecular cause of retinal degeneration in atrd3 mice. Comparison of the two
PDE5/6cd structures shows an overlap between the sildenafil and
Pgamma(70-87)-binding sites, thereby providing critical insights into the side
effects of PDE5 inhibitors on vision.
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