Probing the function, conformational plasticity, and dimer - dimer contacts of the GluR2 ligand-binding core: Studies of 5-substituted willardiines and GluR2 S1S2 in the crystal

Rongsheng Jin, Eric Gouaux

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Numerous naturally occurring and synthetic α-amino acids act as agonists on (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) receptors but nevertheless display significant differences in their functional properties and modes of interaction. The 5-substituted willardiines are a series of compounds that exhibit a range of affinities, act as partial agonists, and give rise to intermediate levels of activation and desensitization. However, the molecular basis for the activities of 5-substituted willardiines has not been conclusively elaborated at the level of atomic resolution. Here we provide insight into the molecular basis of the potency and efficacy elicited by the 5-substituted willardiines on the basis of cocrystal structures with the GluR2 ligand-binding core. We also show that the crystallized ligand-binding core has an affinity for agonists similar to the ligand-binding core in solution. Analysis of multiple crystal lattices suggests modes by which the ligand-binding core dimers interact in the tetrameric receptor. These studies further our understanding of how subtle differences in the structures of agonists are correlated to changes in the conformation of residues and water molecules in the immediate binding pocket and to the degree of domain closure.

Original languageEnglish (US)
Pages (from-to)5201-5213
Number of pages13
JournalBiochemistry
Volume42
Issue number18
DOIs
StatePublished - May 13 2003
Externally publishedYes

Fingerprint

Dimers
Plasticity
Ligands
Crystals
Isoxazoles
AMPA Receptors
Crystal lattices
Conformations
Chemical activation
Amino Acids
Molecules
Water

ASJC Scopus subject areas

  • Biochemistry

Cite this

@article{587b938598774b52b2701abdf440a66a,
title = "Probing the function, conformational plasticity, and dimer - dimer contacts of the GluR2 ligand-binding core: Studies of 5-substituted willardiines and GluR2 S1S2 in the crystal",
abstract = "Numerous naturally occurring and synthetic α-amino acids act as agonists on (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) receptors but nevertheless display significant differences in their functional properties and modes of interaction. The 5-substituted willardiines are a series of compounds that exhibit a range of affinities, act as partial agonists, and give rise to intermediate levels of activation and desensitization. However, the molecular basis for the activities of 5-substituted willardiines has not been conclusively elaborated at the level of atomic resolution. Here we provide insight into the molecular basis of the potency and efficacy elicited by the 5-substituted willardiines on the basis of cocrystal structures with the GluR2 ligand-binding core. We also show that the crystallized ligand-binding core has an affinity for agonists similar to the ligand-binding core in solution. Analysis of multiple crystal lattices suggests modes by which the ligand-binding core dimers interact in the tetrameric receptor. These studies further our understanding of how subtle differences in the structures of agonists are correlated to changes in the conformation of residues and water molecules in the immediate binding pocket and to the degree of domain closure.",
author = "Rongsheng Jin and Eric Gouaux",
year = "2003",
month = "5",
day = "13",
doi = "10.1021/bi020632t",
language = "English (US)",
volume = "42",
pages = "5201--5213",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "18",

}

TY - JOUR

T1 - Probing the function, conformational plasticity, and dimer - dimer contacts of the GluR2 ligand-binding core

T2 - Studies of 5-substituted willardiines and GluR2 S1S2 in the crystal

AU - Jin, Rongsheng

AU - Gouaux, Eric

PY - 2003/5/13

Y1 - 2003/5/13

N2 - Numerous naturally occurring and synthetic α-amino acids act as agonists on (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) receptors but nevertheless display significant differences in their functional properties and modes of interaction. The 5-substituted willardiines are a series of compounds that exhibit a range of affinities, act as partial agonists, and give rise to intermediate levels of activation and desensitization. However, the molecular basis for the activities of 5-substituted willardiines has not been conclusively elaborated at the level of atomic resolution. Here we provide insight into the molecular basis of the potency and efficacy elicited by the 5-substituted willardiines on the basis of cocrystal structures with the GluR2 ligand-binding core. We also show that the crystallized ligand-binding core has an affinity for agonists similar to the ligand-binding core in solution. Analysis of multiple crystal lattices suggests modes by which the ligand-binding core dimers interact in the tetrameric receptor. These studies further our understanding of how subtle differences in the structures of agonists are correlated to changes in the conformation of residues and water molecules in the immediate binding pocket and to the degree of domain closure.

AB - Numerous naturally occurring and synthetic α-amino acids act as agonists on (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazole) propionic acid (AMPA) receptors but nevertheless display significant differences in their functional properties and modes of interaction. The 5-substituted willardiines are a series of compounds that exhibit a range of affinities, act as partial agonists, and give rise to intermediate levels of activation and desensitization. However, the molecular basis for the activities of 5-substituted willardiines has not been conclusively elaborated at the level of atomic resolution. Here we provide insight into the molecular basis of the potency and efficacy elicited by the 5-substituted willardiines on the basis of cocrystal structures with the GluR2 ligand-binding core. We also show that the crystallized ligand-binding core has an affinity for agonists similar to the ligand-binding core in solution. Analysis of multiple crystal lattices suggests modes by which the ligand-binding core dimers interact in the tetrameric receptor. These studies further our understanding of how subtle differences in the structures of agonists are correlated to changes in the conformation of residues and water molecules in the immediate binding pocket and to the degree of domain closure.

UR - http://www.scopus.com/inward/record.url?scp=0038219813&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038219813&partnerID=8YFLogxK

U2 - 10.1021/bi020632t

DO - 10.1021/bi020632t

M3 - Article

C2 - 12731861

AN - SCOPUS:0038219813

VL - 42

SP - 5201

EP - 5213

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 18

ER -