期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 378, 期 3, 页码 673-685出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.03.012
关键词
glutamate receptor; AMPA; partial agonists; NMR; chemical exchange
资金
- NCI NIH HHS [T32 CA009682-15, T32CA09682, T32 CA009682] Funding Source: Medline
- NCRR NIH HHS [S10 RR008438, S10 RR002781, P41RR02301, P41 RR002301-19, P41 RR002301] Funding Source: Medline
- NIGMS NIH HHS [GM068935, R01 GM068935-04, P41GM66326, P41 GM066326, R01 GM068935, P41 GM066326-05] Funding Source: Medline
Glutamate receptors mediate neuronal intercommunication in the central nervous system by coupling extracellular neurotransmitter-receptor interactions to ion channel conductivity. To gain insight into structural and dynamical factors that underlie this coupling, solution NMR experiments were performed on the bilobed ligand-binding core of glutamate receptor 2 in complexes with a set of willardiine partial agonists. These agonists are valuable for studying structure-function relationships because their 5-position substituent size is correlated with ligand efficacy and extent of receptor desensitization, whereas the substituent electronegativity is correlated with ligand potency. NMR results show that the protein backbone amide chemical shift deviations correlate mainly with efficacy and extent of desensitization. Pronounced deviations occur at specific residues in the ligand-binding site and in the two helical segments that join the lobes by a disulfide bond. Experiments detecting conformational exchange show that micro- to millisecond timescale motions also occur near the disulfide bond and vary largely with efficacy and extent of desensitization. These results thus identify regions displaying structural and dynamical dissimilarity arising from differences in ligand-protein interactions and lobe closure that may play a critical role in receptor response. Furthermore, measures of line broadening and conformational exchange for a portion of the ligand-binding site correlate with ligand EC50 data. These results do not have any correlate in the currently available crystal structures and thus provide a novel view of ligand-binding events that may be associated with agonist potency differences. (C) 2008 Elsevier Ltd. All rights reserved.
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