Design and synthesis of high-affinity dimeric inhibitors targeting the interactions between gephyrin and inhibitory neurotransmitter receptors
Standard
Design and synthesis of high-affinity dimeric inhibitors targeting the interactions between gephyrin and inhibitory neurotransmitter receptors. / Maric, Hans Michael; Kasaragod, Vikram Babu; Haugaard-Kedström, Linda; Hausrat, Torben Johann; Kneussel, Matthias; Schindelin, Hermann; Strømgaard, Kristian.
in: ANGEW CHEM INT EDIT, Jahrgang 54, Nr. 2, 07.01.2015, S. 490-4.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Design and synthesis of high-affinity dimeric inhibitors targeting the interactions between gephyrin and inhibitory neurotransmitter receptors
AU - Maric, Hans Michael
AU - Kasaragod, Vikram Babu
AU - Haugaard-Kedström, Linda
AU - Hausrat, Torben Johann
AU - Kneussel, Matthias
AU - Schindelin, Hermann
AU - Strømgaard, Kristian
N1 - © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/1/7
Y1 - 2015/1/7
N2 - Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor-derived minimal gephyrin-binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220-fold enhancement of the gephyrin affinity (KD=6.8 nM). In X-ray crystal structures we visualized the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes. Thus, we defined the molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay.
AB - Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor-derived minimal gephyrin-binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220-fold enhancement of the gephyrin affinity (KD=6.8 nM). In X-ray crystal structures we visualized the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes. Thus, we defined the molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay.
U2 - 10.1002/anie.201409043
DO - 10.1002/anie.201409043
M3 - SCORING: Journal article
C2 - 25413248
VL - 54
SP - 490
EP - 494
JO - ANGEW CHEM INT EDIT
JF - ANGEW CHEM INT EDIT
SN - 1433-7851
IS - 2
ER -