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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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PDB id:
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| Name: |
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Signaling protein
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Title:
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Structure of dncs-1 bound to the ncs-1/ric8a protein/protein interaction regulator igs-1.76
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Structure:
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Fi18190p1. Chain: a. Synonym: frequenin 2,isoform a,isoform b,isoform c,isoform d. Engineered: yes. Mutation: yes
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Source:
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Drosophila melanogaster. Fruit fly. Organism_taxid: 7227. Gene: frq2, dmel\cg5907, frq, frq, frq2, frq2-ra, cg5907, dmel_cg5907. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.82Å
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R-factor:
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0.191
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R-free:
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0.232
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Authors:
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M.J.Sanchez-Barrena,M.Daniel,L.Infantes
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Key ref:
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C.Roca
et al.
(2018).
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.
J Med Chem,
61,
5910-5921.
PubMed id:
DOI:
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Date:
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11-Oct-17
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Release date:
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29-Aug-18
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PROCHECK
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Headers
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References
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Q9VWX8
(Q9VWX8_DROME) -
Frequenin-2 from Drosophila melanogaster
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Seq:
Struc:
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187 a.a.
183 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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DOI no:
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J Med Chem
61:5910-5921
(2018)
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PubMed id:
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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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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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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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Links
