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PDBsum entry 2qyn
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References listed in PDB file
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Key reference
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Title
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Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors.
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Authors
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H.Wang,
M.S.Peng,
Y.Chen,
J.Geng,
H.Robinson,
M.D.Houslay,
J.Cai,
H.Ke.
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Ref.
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Biochem J, 2007,
408,
193-201.
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PubMed id
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Abstract
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PDE4 (phosphodiesterase-4)-selective inhibitors have attracted much attention as
potential therapeutics for the treatment of both depression and major
inflammatory diseases, but their practical application has been compromised by
side effects. A possible cause for the side effects is that current
PDE4-selective inhibitors similarly inhibit isoforms from all four PDE4
subfamilies. The development of PDE4 subfamily-selective inhibitors has been
hampered by a lack of structural information. In the present study, we rectify
this by providing the crystal structures of the catalytic domains of PDE4A,
PDE4B and PDE4D in complex with the PDE4 inhibitor NVP
{4-[8-(3-nitrophenyl)-[1,7]naphthyridin-6-yl]benzoic acid} as well as the
unliganded PDE4C structure. NVP binds in the same conformation to the deep cAMP
substrate pocket and interacts with the same residues in each instance. However,
detailed structural comparison reveals significant conformational differences.
Although the active sites of PDE4B and PDE4D are mostly comparable, PDE4A shows
significant displacements of the residues next to the invariant glutamine
residue that is critical for substrate and inhibitor binding. PDE4C appears to
be more distal from other PDE4 subfamilies, with certain key residues being
disordered. Our analyses provide the first structural basis for the development
of PDE4 subfamily-selective inhibitors.
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