Molecular dynamics simulations of the conformational. changes of the glutamate receptor ligand-binding core in the presence of glutamate and kainate

Mendieta, J Ramirez, G Gago, F

J. Mendieta et al., Molecular dynamics simulations of the conformational. changes of the glutamate receptor ligand-binding core in the presence of glutamate and kainate, PROTEINS, 44(4), 2001, pp. 460-469

38

INGLESE

Article

Biochemistry & Biophysics

PROTEINS-STRUCTURE FUNCTION AND GENETICS

0887-3585 → ACNP

44

4

2001

460 - 469

ISI

0887-3585(20010901)44:4<460:MDSOTC>2.0.ZU;2-#

Excitatory synaptic transmission is mediated by ionotropic glutamate recept ors (iGluRs) through the induced transient opening of transmembrane ion cha nnels. The three-dimensional structure of the extracellular ligand-binding core of iGluRs shares the overall features of bacterial periplasmic binding proteins (PBPs). In both families of proteins, the ligand-binding site is arranged in two domains separated by a cleft and connected by two peptide s tretches. PBPs undergo a typical hinge motion of the two domains associated with ligand binding that leads to a conformational change from an open to a closed form. The common architecture suggests a similar closing mechanism in the ligand-binding core of iGluRs induced by the binding of specific ag onists. Starting from the experimentally determined kainate-bound closed fo rm of the S1S2 GluR2 construct, we have studied by means of molecular dynam ics simulations the opening motion of the ligand-binding core in the presen ce and in the absence of both glutamate and kainate. Our results suggest th at the opening/closing interdomain hinge motions are coupled to conformatio nal changes in the insertion region of the transmembrane segments. These ch anges are triggered by the interaction of the agonists with the essential G lu 209 residue. A plausible mechanism for the coupling of agonist binding t o channel gating is discussed. Proteins 2001;44:460-469. (C) 2001 Wiley-Lis s, Inc.