Structural basis for AMPA receptor activation and ligand selectivity: crystal structures of five agonist complexes with the GluR2 ligand-binding core
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Structural basis for AMPA receptor activation and ligand selectivity : crystal structures of five agonist complexes with the GluR2 ligand-binding core. / Hogner, A; Kastrup, Jette Sandholm Jensen; Jin, R; Liljefors, T; Mayer, M L; Egebjerg, J; Larsen, Ingrid K.; Gouaux, E.
In: Journal of Molecular Biology, Vol. 322, No. 1, 06.09.2002, p. 93-109.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural basis for AMPA receptor activation and ligand selectivity
T2 - crystal structures of five agonist complexes with the GluR2 ligand-binding core
AU - Hogner, A
AU - Kastrup, Jette Sandholm Jensen
AU - Jin, R
AU - Liljefors, T
AU - Mayer, M L
AU - Egebjerg, J
AU - Larsen, Ingrid K.
AU - Gouaux, E
PY - 2002/9/6
Y1 - 2002/9/6
N2 - Glutamate is the principal excitatory neurotransmitter within the mammalian CNS, playing an important role in many different functions in the brain such as learning and memory. In this study, a combination of molecular biology, X-ray structure determinations, as well as electrophysiology and binding experiments, has been used to increase our knowledge concerning the ionotropic glutamate receptor GluR2 at the molecular level. Five high-resolution X-ray structures of the ligand-binding domain of GluR2 (S1S2J) complexed with the three agonists (S)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol-4-yl]propionic acid (2-Me-Tet-AMPA), (S)-2-amino-3-(3-carboxy-5-methylisoxazol-4-yl)propionic acid (ACPA), and (S)-2-amino-3-(4-bromo-3-hydroxy-isoxazol-5-yl)propionic acid (Br-HIBO), as well as of a mutant thereof (S1S2J-Y702F) in complex with ACPA and Br-HIBO, have been determined. The structures reveal that AMPA agonists with an isoxazole moiety adopt different binding modes in the receptor, dependent on the substituents of the isoxazole. Br-HIBO displays selectivity among different AMPA receptor subunits, and the design and structure determination of the S1S2J-Y702F mutant in complex with Br-HIBO and ACPA have allowed us to explain the molecular mechanism behind this selectivity and to identify key residues for ligand recognition. The agonists induce the same degree of domain closure as AMPA, except for Br-HIBO, which shows a slightly lower degree of domain closure. An excellent correlation between domain closure and efficacy has been obtained from electrophysiology experiments undertaken on non-desensitising GluR2i(Q)-L483Y receptors expressed in oocytes, providing strong evidence that receptor activation occurs as a result of domain closure. The structural results, combined with the functional studies on the full-length receptor, form a powerful platform for the design of new selective agonists.
AB - Glutamate is the principal excitatory neurotransmitter within the mammalian CNS, playing an important role in many different functions in the brain such as learning and memory. In this study, a combination of molecular biology, X-ray structure determinations, as well as electrophysiology and binding experiments, has been used to increase our knowledge concerning the ionotropic glutamate receptor GluR2 at the molecular level. Five high-resolution X-ray structures of the ligand-binding domain of GluR2 (S1S2J) complexed with the three agonists (S)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol-4-yl]propionic acid (2-Me-Tet-AMPA), (S)-2-amino-3-(3-carboxy-5-methylisoxazol-4-yl)propionic acid (ACPA), and (S)-2-amino-3-(4-bromo-3-hydroxy-isoxazol-5-yl)propionic acid (Br-HIBO), as well as of a mutant thereof (S1S2J-Y702F) in complex with ACPA and Br-HIBO, have been determined. The structures reveal that AMPA agonists with an isoxazole moiety adopt different binding modes in the receptor, dependent on the substituents of the isoxazole. Br-HIBO displays selectivity among different AMPA receptor subunits, and the design and structure determination of the S1S2J-Y702F mutant in complex with Br-HIBO and ACPA have allowed us to explain the molecular mechanism behind this selectivity and to identify key residues for ligand recognition. The agonists induce the same degree of domain closure as AMPA, except for Br-HIBO, which shows a slightly lower degree of domain closure. An excellent correlation between domain closure and efficacy has been obtained from electrophysiology experiments undertaken on non-desensitising GluR2i(Q)-L483Y receptors expressed in oocytes, providing strong evidence that receptor activation occurs as a result of domain closure. The structural results, combined with the functional studies on the full-length receptor, form a powerful platform for the design of new selective agonists.
KW - Animals
KW - Binding Sites
KW - Crystallography, X-Ray
KW - Electrophysiology
KW - Hydrogen Bonding
KW - Ion Channel Gating
KW - Ion Channels
KW - Ligands
KW - Models, Molecular
KW - Molecular Structure
KW - Movement
KW - Mutation
KW - Oocytes
KW - Protein Structure, Quaternary
KW - Protein Structure, Tertiary
KW - Protein Subunits
KW - Receptors, AMPA
KW - Static Electricity
KW - Structure-Activity Relationship
KW - Substrate Specificity
M3 - Journal article
C2 - 12215417
VL - 322
SP - 93
EP - 109
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 1
ER -
ID: 44729560