TY - JOUR
T1 - Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor
AU - Laulumaa, Saara
AU - Hansen, Kathrine Voigt
AU - Masternak, Magdalena
AU - Drapier, Thomas
AU - Francotte, Pierre
AU - Pirotte, Bernard
AU - Frydenvang, Karla
AU - Kastrup, Jette Sandholm
PY - 2019/3/14
Y1 - 2019/3/14
N2 - The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TDPAM02, with nanomolar potency at GluA2. Using X-ray crystallography, TDPAM01 and TDPAM02 were crystallized in the ligand-binding domain of the GluA2 flop isoform as well as in the flip-like mutant N775S and the preformed dimer L504Y-N775S. In all structures, one modulator molecule binds at the dimer interface with two characteristic hydrogen bonds being formed from the modulator to Pro515. Whereas the GluA2 dimers and modulator binding mode are similar when crystallized in the presence of l-glutamate, the shape of the binding site differs when no l-glutamate is present. TDPAM02 has no effect on domain closure in both apo and l-glutamate bound GluA2 dimers compared to structures without modulator.
AB - The ionotropic glutamate receptor GluA2 is considered to be an attractive target for positive allosteric modulation for the development of pharmacological tools or cognitive enhancers. Here, we report a detailed structural characterization of two recently reported dimeric positive allosteric modulators, TDPAM01 and TDPAM02, with nanomolar potency at GluA2. Using X-ray crystallography, TDPAM01 and TDPAM02 were crystallized in the ligand-binding domain of the GluA2 flop isoform as well as in the flip-like mutant N775S and the preformed dimer L504Y-N775S. In all structures, one modulator molecule binds at the dimer interface with two characteristic hydrogen bonds being formed from the modulator to Pro515. Whereas the GluA2 dimers and modulator binding mode are similar when crystallized in the presence of l-glutamate, the shape of the binding site differs when no l-glutamate is present. TDPAM02 has no effect on domain closure in both apo and l-glutamate bound GluA2 dimers compared to structures without modulator.
U2 - 10.1021/acsmedchemlett.8b00369
DO - 10.1021/acsmedchemlett.8b00369
M3 - Journal article
C2 - 30891120
SN - 1948-5875
VL - 10
SP - 243
EP - 247
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 3
ER -