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A molecular envelope of the ligand-binding domain of a glutamate receptor in the presence and absence of agonist

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Abele,  Rupert
Max Planck Research Group Ion Channel Structure (Dean R. Madden), Max Planck Institute for Medical Research, Max Planck Society;

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Madden,  Dean R.
Max Planck Research Group Ion Channel Structure (Dean R. Madden), Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Abele, R., Svergun, D., Keinänen, K., Koch, M. J., & Madden, D. R. (1999). A molecular envelope of the ligand-binding domain of a glutamate receptor in the presence and absence of agonist. Biochemistry, 38(34), 10949-10957. doi:10.1021/bi982928y.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0024-0781-2
Abstract
Solution scattering studies were performed on a ligand-binding domain (S1S2) of a glutamate receptor ion channel (GluR) in order to study GluR-binding and signal-transduction mechanisms. The core of the ligand-binding domain is homologous to prokaryotic periplasmic binding proteins (PBP), whose binding mechanism involves a dramatic cleft closure: the Venus flytrap. Several models of GluR function have proposed that a similar cleft closure is induced by agonist binding. We have directly tested this putative functional homology by measuring the radius of gyration of S1S2 in the presence and absence of saturating concentrations of agonists. In contrast to the PBP, S1S2 shows no reduction in radius of gyration upon agonist binding, excluding a comparably large conformational change. Furthermore, we determined an ab initio molecular envelope for our S1S2 construct, which also contains the peptides that connect the PBP homology core to the three transmembrane domains and to an N-terminal domain. By fitting an atomic model of the ligand-binding domain core to the envelope of our extended construct, we were able to establish the likely position of these connecting peptides. Their positions relative to one another and to the expected sites of an agonist-induced conformational change suggest that ion channel gating and desensitization may involve more subtle and complex mechanisms than have been assumed based on the structural homology to the PBP