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The ligand-binding domain (LBD) from the ionotropic glutamate receptor subtype 2 (GluR2) has been shown to adopt a range of ligand-dependent conformational states. These states have been described in terms of the rotation required to fit subdomain (lobe) 2 following superposition of subdomain (lobe) 1. The LBD has a closed-cleft conformation for full agonists, but partial agonists induce a range of closure, which in turn controls the open probability of discrete subconductance states in the full-length receptor. Although this description is useful, it may not account for all physiologically important motions that the receptor undergoes. We have used an approach that combines the methods of essential dynamics and rigid-body dynamics to analyze 124 monomer domains from 55 crystal structures of the GluR2 LBD. We are able to show that partial agonists also induce a significant amount of twist that would not be anticipated using one rotational descriptor between apo and full-agonist-bound states. Furthermore, one of the crystal structures (chain B from 1P1U, the GluR2 L650T-AMPA complex), which has been suggested to represent an agonist-bound inactive form of the receptor, lies at the extreme of this twist motion. We suggest that partial agonists not only prevent full closure but also move the receptor closer to this inactive state. We demonstrate additionally how the method can be used to compare the results of molecular dynamics simulations with the crystallographic data and the extent to which the conformational space explored by both overlaps.

Original publication

DOI

10.1002/prot.21941

Type

Journal article

Journal

Proteins

Publication Date

07/2008

Volume

72

Pages

434 - 446

Keywords

Computer Simulation, Crystallography, X-Ray, Dimerization, Ligands, Models, Molecular, Protein Structure, Tertiary, Receptors, AMPA