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PDBsum entry 6fdc
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References listed in PDB file
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Key reference
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Title
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Molecular bases of pde4d inhibition by memory-Enhancing gebr library compounds.
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Authors
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T.Prosdocimi,
L.Mollica,
S.Donini,
M.S.Semrau,
A.P.Lucarelli,
E.Aiolfi,
A.Cavalli,
P.Storici,
S.Alfei,
C.Brullo,
O.Bruno,
E.Parisini.
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Ref.
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Biochemistry, 2018,
57,
2876-2888.
[DOI no: ]
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PubMed id
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Abstract
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Selected members of the large rolipram-related GEBR family of type 4
phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term
potentiation and to improve memory functions without causing emetic-like
behavior in rodents. Despite their micromolar-range binding affinities and their
promising pharmacological and toxicological profiles, few if any
structure-activity relationship studies have been performed to elucidate the
molecular bases of their action. Here, we report the crystal structure of a
number of GEBR library compounds in complex with the catalytic domain of PDE4D
as well as their inhibitory profiles for both the long PDE4D3 isoform and the
catalytic domain alone. Furthermore, we assessed the stability of the observed
ligand conformations in the context of the intact enzyme using molecular
dynamics simulations. The longer and more flexible ligands appear to be capable
of forming contacts with the regulatory portion of the enzyme, thus possibly
allowing some degree of selectivity between the different PDE4 isoforms.
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