PDBsum entry 3bfu

Membrane protein

PDB id: 3bfu

Contents

Protein chains

262 a.a.

Ligands

R2P ×4

Waters ×1218

References listed in PDB file

Key reference

Title

Structures of the ligand-Binding core of iglur2 in complex with the agonists (r)- And (s)-2-Amino-3-(4-Hydroxy-1,2,5-Thiadiazol-3-Yl)propionic acid explain their unusual equipotency.

Authors

M.Beich-Frandsen, D.S.Pickering, O.Mirza, T.N.Johansen, J.Greenwood, B.Vestergaard, A.Schousboe, M.Gajhede, T.Liljefors, J.S.Kastrup.

Ref.

J Med Chem, 2008, 51, 1459-1463.

PubMed id

18269227

Abstract

AMPA-type ionotropic glutamate receptors generally display high stereoselectivity in agonist binding. However, the stereoisomers of 2-amino-3-(4-hydroxy-1,2,5-thiadiazol-3-yl)propionic acid (TDPA) have similar enantiopharmacology. To understand this observation, we have determined the X-ray structures of ( R)-TDPA and ( S)-TDPA in complex with the ligand-binding core of iGluR2 and investigated the binding pharmacology at AMPA and kainate receptors. Both enantiomers induce full domain closure in iGluR2 but adopt different conformations when binding to the receptor, which may explain the similar enantiopharmacology.

Secondary reference #1

Title

Mechanisms for activation and antagonism of an ampa-Sensitive glutamate receptor: crystal structures of the glur2 ligand binding core.

Authors

N.Armstrong, E.Gouaux.

Ref.

Neuron, 2000, 28, 165-181. [DOI no: 10.1016/S0896-6273(00)00094-5]

PubMed id

11086992

Figure 1.
Figure 1. Ligand Binding Constants for S1S2J(A) Domain structure of iGluRs showing the S1 and S2 segments in turquoise and pink, respectively. “Cut” and “link” denote the edges of the S1S2 construct.(B) K[D] for ^3H-AMPA binding was 24.8 ± 1.8 nM.(C) IC[50] for displacement of ^3H-AMPA by glutamate, kainate, and DNQX were 821 nM, 14.5 μM, and 998 nM, respectively.

Figure 2.
Figure 2. Superposition of the Expanded Cleft Structures and Stereo View of the DNQX Binding Site(A) The two apo molecules (ApoA and ApoB) and two DNQX molecules (DNQXA and DNQXB) in each asymmetric unit were superimposed using only Cα atoms from domain 1. Apo protomers are shaded red and pink while DNQX protomers are colored light green and dark green. DNQX is depicted in black, and selected side chains from DNQXB are shown in dark green. The conformational change undergone by Glu-705 is illustrated by comparing its orientation in ApoB and DNQXB. In the apo state, Glu-705 accepts hydrogen bonds from the side chains of Lys-730 and Thr-655.(B) The chemical structure of DNQX and F[o]-F[c] omit electron density for DNQX and sulfate contoured at 2.5 σ.(C) Stereo image of the interactions between DNQX, sulfate, and S1S2J. DNQXB side chains are colored gray. Water molecules are shown as green balls. DNQX is colored black. Hydrogen bonds between DNQX, sulfate, and S1S2J are indicated by black dashed lines.

The above figures are reproduced from the cited reference with permission from Cell Press