PDBsum entry 1mqh

Membrane protein

PDB id: 1mqh

Contents

Protein chain

260 a.a. *

Ligands

BWD

Waters ×241

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structural basis for partial agonist action at ionotropic glutamate receptors.

Authors

R.Jin, T.G.Banke, M.L.Mayer, S.F.Traynelis, E.Gouaux.

Ref.

Nat Neurosci, 2003, 6, 803-810. [DOI no: 10.1038/nn1091]

PubMed id

12872125

Abstract

An unresolved problem in understanding neurotransmitter receptor function concerns the mechanism(s) by which full and partial agonists elicit different amplitude responses at equal receptor occupancy. The widely held view of 'partial agonism' posits that resting and active states of the receptor are in equilibrium, and partial agonists simply do not shift the equilibrium toward the active state as efficaciously as full agonists. Here we report findings from crystallographic and electrophysiological studies of the mechanism of activation of an AMPA-subtype glutamate receptor ion channel. In these experiments, we used 5-substituted willardiines, a series of partial agonists that differ by only a single atom. Our results show that the GluR2 ligand-binding core can adopt a range of ligand-dependent conformational states, which in turn control the open probability of discrete subconductance states of the intact ion channel. Our findings thus provide a structure-based model of partial agonism.

Figure 1.
Figure 1. Ionotropic glutamate receptor domain organization and agonist structure. (a) iGluR domain organization. Polypeptide segments S1 and S2 comprise the water-soluble, ligand-binding core and the S1S2J construct studied here includes residues 392 -506 (S1) and 632 -775 (S2) linked together by a Gly -Thr dipeptide. The amino terminal domain (ATD) and the transmembrane segments are not contained within the S1S2J construct. (b) Chemical structures of glutamate and 5-substituted willardiines.

Figure 3.
Figure 3. Electron density |F[o]| - |F[c]| 'omit' maps for willardiines and selected interacting residues. (a) HW complex. (b) FW complex. (c) BrW complex. (d) IW complex. Maps are contoured at 4.0 for HW, FW and BrW complexes, and 3.2 for IW complex.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Neurosci (2003, 6, 803-810) copyright 2003.

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