Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor. / Laulumaa, Saara; Hansen, Kathrine Voigt; Masternak, Magdalena; Drapier, Thomas; Francotte, Pierre; Pirotte, Bernard; Frydenvang, Karla; Kastrup, Jette Sandholm.

In: ACS Medicinal Chemistry Letters, Vol. 10, No. 3, 14.03.2019, p. 243-247.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Laulumaa, S, Hansen, KV, Masternak, M, Drapier, T, Francotte, P, Pirotte, B, Frydenvang, K & Kastrup, JS 2019, 'Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor', ACS Medicinal Chemistry Letters, vol. 10, no. 3, pp. 243-247. https://doi.org/10.1021/acsmedchemlett.8b00369

APA

Laulumaa, S., Hansen, K. V., Masternak, M., Drapier, T., Francotte, P., Pirotte, B., Frydenvang, K., & Kastrup, J. S. (2019). Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor. ACS Medicinal Chemistry Letters, 10(3), 243-247. https://doi.org/10.1021/acsmedchemlett.8b00369

Vancouver

Laulumaa S, Hansen KV, Masternak M, Drapier T, Francotte P, Pirotte B et al. Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor. ACS Medicinal Chemistry Letters. 2019 Mar 14;10(3):243-247. https://doi.org/10.1021/acsmedchemlett.8b00369

Author

Laulumaa, Saara ; Hansen, Kathrine Voigt ; Masternak, Magdalena ; Drapier, Thomas ; Francotte, Pierre ; Pirotte, Bernard ; Frydenvang, Karla ; Kastrup, Jette Sandholm. / Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor. In: ACS Medicinal Chemistry Letters. 2019 ; Vol. 10, No. 3. pp. 243-247.

Bibtex

@article{d00bf8e466ed4cafbd4051e07dde449c,
title = "Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor",
abstract = "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.",
author = "Saara Laulumaa and Hansen, {Kathrine Voigt} and Magdalena Masternak and Thomas Drapier and Pierre Francotte and Bernard Pirotte and Karla Frydenvang and Kastrup, {Jette Sandholm}",
year = "2019",
month = mar,
day = "14",
doi = "10.1021/acsmedchemlett.8b00369",
language = "English",
volume = "10",
pages = "243--247",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "3",

}

RIS

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

VL - 10

SP - 243

EP - 247

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 3

ER -

ID: 221759555