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PDBsum entry 6epa
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Signaling protein
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PDB id
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6epa
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References listed in PDB file
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Key reference
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Title
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Deciphering the inhibition of the neuronal calcium sensor 1 and the guanine exchange factor ric8a with a small phenothiazine molecule for the rational generation of therapeutic synapse function regulators.
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Authors
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C.Roca,
L.Martinez-González,
M.Daniel-Mozo,
J.Sastre,
L.Infantes,
A.Mansilla,
A.Chaves-Sanjuan,
J.M.González-Rubio,
C.Gil,
F.J.Cañada,
A.Martinez,
M.J.Sanchez-Barrena,
N.E.Campillo.
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Ref.
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J Med Chem, 2018,
61,
5910-5921.
[DOI no: ]
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PubMed id
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Abstract
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Protein-protein interactions (PPIs) are known to play an essential role between
the neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor Ric8a to
regulate synapse function, emerging as a druggable interface for synaptopathies
such as the fragile X syndrome (FXS). Recently, the phenothiazine FD44 has been
identified as an inhibitor of this PPI, decreasing the abnormally high synapse
number and enhancing associative learning in a FXS animal model. Here, we have
integrated advanced experimental and computational studies to obtain important
structural insights into Drosophila NCS-1/FD44 recognition to understand the
basis of its affinity and specificity and generate improved PPI regulators. This
has allowed the identification of a new small drug-like molecule, IGS-1.76,
which efficiently inhibits the human NCS-1/Ric8a complex with improved binding
potency. The crystal structure of the Drosophila NCS-1/IGS-1.76 complex
demonstrates that the new inhibitor, although chemically different from FD44,
shares the same mechanism of action and constitutes a new hit candidate for FXS.
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