Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites. / Kaae, Birgitte Høiriis; Harpsøe, Kasper; Kastrup, Jette Sandholm Jensen; Sanz, Alberto Contreras; Pickering, Darryl Scott; Metzler, Bjørn; Clausen, Rasmus Prætorius; Gajhede, Michael; Sauerberg, Per; Liljefors, Tommy; Madsen, Ulf.

In: Chemistry & Biology, Vol. 14, No. 11, 2007, p. 1294-303.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Kaae, BH, Harpsøe, K, Kastrup, JSJ, Sanz, AC, Pickering, DS, Metzler, B, Clausen, RP, Gajhede, M, Sauerberg, P, Liljefors, T & Madsen, U 2007, 'Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites', Chemistry & Biology, vol. 14, no. 11, pp. 1294-303. https://doi.org/10.1016/j.chembiol.2007.10.012

APA

Kaae, B. H., Harpsøe, K., Kastrup, J. S. J., Sanz, A. C., Pickering, D. S., Metzler, B., ... Madsen, U. (2007). Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites. Chemistry & Biology, 14(11), 1294-303. https://doi.org/10.1016/j.chembiol.2007.10.012

Vancouver

Kaae BH, Harpsøe K, Kastrup JSJ, Sanz AC, Pickering DS, Metzler B et al. Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites. Chemistry & Biology. 2007;14(11):1294-303. https://doi.org/10.1016/j.chembiol.2007.10.012

Author

Kaae, Birgitte Høiriis ; Harpsøe, Kasper ; Kastrup, Jette Sandholm Jensen ; Sanz, Alberto Contreras ; Pickering, Darryl Scott ; Metzler, Bjørn ; Clausen, Rasmus Prætorius ; Gajhede, Michael ; Sauerberg, Per ; Liljefors, Tommy ; Madsen, Ulf. / Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites. In: Chemistry & Biology. 2007 ; Vol. 14, No. 11. pp. 1294-303.

Bibtex

@article{2d2927b0015611ddbee902004c4f4f50,
title = "Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites",
abstract = "Dimeric positive allosteric modulators of ionotropic glutamate receptors were designed, synthesized, and characterized pharmacologically in electrophysiological experiments. The designed compounds are dimers of arylpropylsulfonamides and have been constructed without a linker. The monomeric arylpropylsulfonamides were derived from known modulators and target the cyclothiazide-binding site at the AMPA receptors. The three stereoisomers--R,R, meso, and S,S--of the two constructed dimers were prepared, and in vitro testing showed the R,R forms to be the most potent stereoisomers. The biarylpropylsulfonamides have dramatically increased potencies, more than three orders of magnitude higher than the corresponding monomers. Dimer (R,R)-2a was cocrystallized with the GluR2-S1S2J construct, and an X-ray crystallographic analysis showed (R,R)-2a to bridge two identical binding pockets on two neighboring GluR2 subunits. Thus, this is biostructural evidence of a homomeric dimer bridging two identical receptor-binding sites.",
keywords = "Former Faculty of Pharmaceutical Sciences, Binding Sites, Crystallography, X-Ray, Dimerization, Ligands, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Receptors, AMPA, Stereoisomerism",
author = "Kaae, {Birgitte H{\o}iriis} and Kasper Harps{\o}e and Kastrup, {Jette Sandholm Jensen} and Sanz, {Alberto Contreras} and Pickering, {Darryl Scott} and Bj{\o}rn Metzler and Clausen, {Rasmus Pr{\ae}torius} and Michael Gajhede and Per Sauerberg and Tommy Liljefors and Ulf Madsen",
year = "2007",
doi = "10.1016/j.chembiol.2007.10.012",
language = "English",
volume = "14",
pages = "1294--303",
journal = "Chemistry and Biology",
issn = "2451-9448",
publisher = "Elsevier",
number = "11",

}

RIS

TY - JOUR

T1 - Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites

AU - Kaae, Birgitte Høiriis

AU - Harpsøe, Kasper

AU - Kastrup, Jette Sandholm Jensen

AU - Sanz, Alberto Contreras

AU - Pickering, Darryl Scott

AU - Metzler, Bjørn

AU - Clausen, Rasmus Prætorius

AU - Gajhede, Michael

AU - Sauerberg, Per

AU - Liljefors, Tommy

AU - Madsen, Ulf

PY - 2007

Y1 - 2007

N2 - Dimeric positive allosteric modulators of ionotropic glutamate receptors were designed, synthesized, and characterized pharmacologically in electrophysiological experiments. The designed compounds are dimers of arylpropylsulfonamides and have been constructed without a linker. The monomeric arylpropylsulfonamides were derived from known modulators and target the cyclothiazide-binding site at the AMPA receptors. The three stereoisomers--R,R, meso, and S,S--of the two constructed dimers were prepared, and in vitro testing showed the R,R forms to be the most potent stereoisomers. The biarylpropylsulfonamides have dramatically increased potencies, more than three orders of magnitude higher than the corresponding monomers. Dimer (R,R)-2a was cocrystallized with the GluR2-S1S2J construct, and an X-ray crystallographic analysis showed (R,R)-2a to bridge two identical binding pockets on two neighboring GluR2 subunits. Thus, this is biostructural evidence of a homomeric dimer bridging two identical receptor-binding sites.

AB - Dimeric positive allosteric modulators of ionotropic glutamate receptors were designed, synthesized, and characterized pharmacologically in electrophysiological experiments. The designed compounds are dimers of arylpropylsulfonamides and have been constructed without a linker. The monomeric arylpropylsulfonamides were derived from known modulators and target the cyclothiazide-binding site at the AMPA receptors. The three stereoisomers--R,R, meso, and S,S--of the two constructed dimers were prepared, and in vitro testing showed the R,R forms to be the most potent stereoisomers. The biarylpropylsulfonamides have dramatically increased potencies, more than three orders of magnitude higher than the corresponding monomers. Dimer (R,R)-2a was cocrystallized with the GluR2-S1S2J construct, and an X-ray crystallographic analysis showed (R,R)-2a to bridge two identical binding pockets on two neighboring GluR2 subunits. Thus, this is biostructural evidence of a homomeric dimer bridging two identical receptor-binding sites.

KW - Former Faculty of Pharmaceutical Sciences

KW - Binding Sites

KW - Crystallography, X-Ray

KW - Dimerization

KW - Ligands

KW - Models, Molecular

KW - Nuclear Magnetic Resonance, Biomolecular

KW - Protein Conformation

KW - Receptors, AMPA

KW - Stereoisomerism

U2 - 10.1016/j.chembiol.2007.10.012

DO - 10.1016/j.chembiol.2007.10.012

M3 - Journal article

C2 - 18022568

VL - 14

SP - 1294

EP - 1303

JO - Chemistry and Biology

JF - Chemistry and Biology

SN - 2451-9448

IS - 11

ER -

ID: 3469632