TY - JOUR

T1 - Rigid body essential X-ray crystallography

T2 - Distinguishing the bend and twist of glutamate receptor ligand binding domains

AU - Bjerrum, Esben Jannik

AU - Biggin, Philip C

N1 - Keywords: Computer Simulation; Crystallography, X-Ray; Dimerization; Ligands; Models, Molecular; Protein Structure, Tertiary; Receptors, AMPA

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1002/prot.21941

DO - 10.1002/prot.21941

M3 - Journal article

C2 - 18214958

VL - 72

SP - 434

EP - 446

JO - Proteins: Structure, Function, and Bioinformatics

JF - Proteins: Structure, Function, and Bioinformatics

SN - 0887-3585

IS - 1

ER -