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PDBsum entry 4n07
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Membrane protein
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PDB id
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4n07
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PDB id:
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| Name: |
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Membrane protein
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Title:
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Crystal structure of the glua2 ligand-binding domain (s1s2j-l483y- n754s) in complex with glutamate and bpam-344 at 1.87 a resolution
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Structure:
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Glutamate receptor 2. Chain: a, b, c. Fragment: unp residues 413-527, unp reisdues 653-796. Synonym: glur-2, ampa-selective glutamate receptor 2, glur-b, glur- k2, glutamate receptor ionotropic, ampa 2, glua2. Engineered: yes. Mutation: yes
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Source:
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Rattus norvegicus. Rat. Organism_taxid: 10116. Strain: rat. Gene: glur2, gria2. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.87Å
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R-factor:
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0.177
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R-free:
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0.211
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Authors:
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A.B.Noerholm,K.Frydenvang,J.S.Kastrup
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Key ref:
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A.B.Nørholm
et al.
(2013).
Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold.
J Med Chem,
56,
8736-8745.
PubMed id:
DOI:
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Date:
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01-Oct-13
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Release date:
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20-Nov-13
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PROCHECK
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Headers
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References
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P19491
(GRIA2_RAT) -
Glutamate receptor 2 from Rattus norvegicus
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Seq:
Struc:
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883 a.a.
262 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 6 residue positions (black
crosses)
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DOI no:
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J Med Chem
56:8736-8745
(2013)
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PubMed id:
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Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold.
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A.B.Nørholm,
P.Francotte,
L.Olsen,
C.Krintel,
K.Frydenvang,
E.Goffin,
S.Challal,
L.Danober,
I.Botez-Pop,
P.Lestage,
B.Pirotte,
J.S.Kastrup.
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ABSTRACT
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Positive allosteric modulators of ionotropic glutamate receptors are potential
compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The
modulators bind within the dimer interface of the ligand-binding domain (LBD)
and stabilize the agonist-bound conformation, thereby slowing receptor
desensitization and/or deactivation. Here we describe the synthesis and
pharmacological testing at GluA2 of a new generation of
3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3
in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by
X-ray crystallography, and the thermodynamics of binding was studied by
isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with
a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the
first time that submicromolar binding affinity has been achieved for this type
of positive allosteric modulator. The major structural factor increasing the
binding affinity of 3 seems to be interactions between the cyclopropyl group of
3 and the backbone of Phe495 and Met496.
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