Structure and affinity of two bicyclic glutamate analogues at AMPA and kainate receptors

Stine Møllerud; Andrea Pinto; Laura Marconi; Karla Andrea Frydenvang; Thor Seneca Thorsen; Saara Kaisa Laulumaa; Raminta Venskutonyte; Nikolaj Winther; Ana Maria Cunado Moral; Lucia Tamborini; Paola Conti; Darryl S Pickering; Jette Sandholm Jensen Kastrup

doi:10.1021/acschemneuro.7b00201

Structure and affinity of two bicyclic glutamate analogues at AMPA and kainate receptors

Stine Møllerud, Andrea Pinto, Laura Marconi, Karla Andrea Frydenvang, Thor Seneca Thorsen, Saara Kaisa Laulumaa, Raminta Venskutonyte, Nikolaj Winther, Ana Maria Cunado Moral, Lucia Tamborini, Paola Conti, Darryl S Pickering, Jette Sandholm Jensen Kastrup

Department of Drug Design and Pharmacology

4 Citations (Scopus)

Abstract

Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with K_i of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold better than that for CIP-AS (K_i of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function.

Original language	English
Journal	A C S Chemical Neuroscience
Volume	8
Issue number	9
Pages (from-to)	2056-2064
Number of pages	9
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.7b00201
Publication status	Published - 20 Sept 2017

Access to Document

10.1021/acschemneuro.7b00201

Cite this

Møllerud, S., Pinto, A., Marconi, L., Frydenvang, K. A., Thorsen, T. S., Laulumaa, S. K., Venskutonyte, R., Winther, N., Cunado Moral, A. M., Tamborini, L., Conti, P., Pickering, D. S., & Kastrup, J. S. J. (2017). Structure and affinity of two bicyclic glutamate analogues at AMPA and kainate receptors. A C S Chemical Neuroscience, 8(9), 2056-2064. https://doi.org/10.1021/acschemneuro.7b00201

Møllerud, S, Pinto, A, Marconi, L, Frydenvang, KA , Thorsen, TS, Laulumaa, SK, Venskutonyte, R, Winther, N, Cunado Moral, AM, Tamborini, L, Conti, P, Pickering, DS & Kastrup, JSJ 2017, 'Structure and affinity of two bicyclic glutamate analogues at AMPA and kainate receptors', A C S Chemical Neuroscience, vol. 8, no. 9, pp. 2056-2064. https://doi.org/10.1021/acschemneuro.7b00201

@article{0a06be0724cc44cdb7813af00d1f19d2,

title = "Structure and affinity of two bicyclic glutamate analogues at AMPA and kainate receptors",

abstract = "Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with Ki of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold better than that for CIP-AS (Ki of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function.",

author = "Stine M{\o}llerud and Andrea Pinto and Laura Marconi and Frydenvang, {Karla Andrea} and Thorsen, {Thor Seneca} and Laulumaa, {Saara Kaisa} and Raminta Venskutonyte and Nikolaj Winther and {Cunado Moral}, {Ana Maria} and Lucia Tamborini and Paola Conti and Pickering, {Darryl S} and Kastrup, {Jette Sandholm Jensen}",

year = "2017",

month = sep,

day = "20",

doi = "10.1021/acschemneuro.7b00201",

language = "English",

volume = "8",

pages = "2056--2064",

journal = "A C S Chemical Neuroscience",

issn = "1948-7193",

publisher = "American Chemical Society",

number = "9",

}

TY - JOUR

T1 - Structure and affinity of two bicyclic glutamate analogues at AMPA and kainate receptors

AU - Møllerud, Stine

AU - Pinto, Andrea

AU - Marconi, Laura

AU - Frydenvang, Karla Andrea

AU - Thorsen, Thor Seneca

AU - Laulumaa, Saara Kaisa

AU - Venskutonyte, Raminta

AU - Winther, Nikolaj

AU - Cunado Moral, Ana Maria

AU - Tamborini, Lucia

AU - Conti, Paola

AU - Pickering, Darryl S

AU - Kastrup, Jette Sandholm Jensen

PY - 2017/9/20

Y1 - 2017/9/20

N2 - Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with Ki of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold better than that for CIP-AS (Ki of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function.

AB - Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer's disease, epilepsy and depression. To understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with Ki of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold better than that for CIP-AS (Ki of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function.

U2 - 10.1021/acschemneuro.7b00201

DO - 10.1021/acschemneuro.7b00201

M3 - Journal article

C2 - 28691798

SN - 1948-7193

VL - 8

SP - 2056

EP - 2064

JO - A C S Chemical Neuroscience

JF - A C S Chemical Neuroscience

IS - 9

ER -

Structure and affinity of two bicyclic glutamate analogues at AMPA and kainate receptors

Abstract

Access to Document

Fingerprint

Cite this