Editors' ChoiceStructural Biology

Conformations of Glutamate Receptors

Science's STKE  31 Oct 2000:
Vol. 2000, Issue 56, pp. tw2
DOI: 10.1126/stke.2000.56.tw2

The metabotropic glutamate receptor (mGluR) belongs to the family of G protein-coupled receptors (GPCRs). However, this group of GPCRs has a fundamental difference in the manner in which ligand binds compared with the well-characterized rhodopsin-like GPCRs. The ligand-binding domain, which is comprised of the LB1 and LB2 domains, is part of the extracellular domain in the mGluR, whereas in rhodopsin the ligand-binding domain is in a pocket created by the transmembrane helices. Kunishima et al. crystallized the ligand-binding region of the mGluR and found three stable crystal structures: two unliganded forms (free forms I and II) and one liganded form (complex). Similar to mGluR in cells, all of the crystals are dimers of two molecules connected by a disulfide bridge. The complex form and free form II have very similar overall conformations in which the two LB2 domains are close together, whereas the free form I is substantially different, with the two LB2 domains farther apart. The data suggest that the receptor exists in multiple conformations and that glutamate binding stabilizes the closed conformation found in the complex form and free form II, which constitutes the active state of the receptor. These results have implications for understanding the mechanism of activation of other receptors that bind small ligands in extracellular ligand-binding domains.

Kunishima, N., Shimada, Y., Tsuji, Y., Sato, T., Yamamoto, M., Kumasaka, T., Nakanishi, S., Jingami, H., and Morikawa, K. (2000) Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407: 971-977. [Online Journal]