The VFT Domain

The VFT domain is comprised of two lobes with a/p topology. In three articles [73-75] between 2000 and 2007, the same group published X-ray structures of VFT regions of mGluR1, mGluR3, and mGluR7, thereby spanning the I, II, and III subgroups, respectively (see Table 16.1). Included in these structures are examples of different domain conformations (open and closed), inter-domain orientations, and active-site occupations that can now serve as a broad suite of templates for direct use in drug design or homology modeling of other Class C targets of interest that are not exemplified. Examination of some of these structures illustrates the emerging picture. For mGluR1, X-ray structures are available for the two lobes in closed and open conformations (see Figs. 16.4 and 16.5). Both the closed and open conformations are found with the active site bound with glutamate or an empty (apo) active site. This supports earlier evidence that there is an equilibrium between the two conformations, and the role of the agonist is to shift the equilibrium toward the more active conformation, believed to be the closed conformation. Consistent

Figure 16.5 View of the rat mGluRl EC domain in the (a) closed and (b) open conformations with glutamate bound (taken from chains A and B of PDB entry 1EWK, respectively).

with this, the open conformation is found with the antagonist (S)-(a)-me thy l-4-carboxyphenylglycine (S-MCPG) bound. Closing of the VFT of one monomer (protomer) is believed to play a role in activation, but the relative structures between the VFT regions of the protomers in the dimer, as well as their relative orientations, were also found to change, and these changes are believed to play a role in the activation process [73, 75, 76]. For example, it has been suggested that these EC changes could affect the interactions, and thereby possibly the conformation, of the 7TM regions.

As expected, the active site is very polar. Comparisons of the active sites show that despite the use of a common endogenous ligand, there are differences between the X-ray structures. Thus, even glutamate binds slightly differently to the mGluRl and mGluR3 VFT domains. The highly polar active site makes varying use of water molecules to bind different agonists in the X-ray structures of mGluR3 complexes. Also, comparisons of the X-ray structures showed that differences between residues in the active site explain the mGluR3 selectivity of DCG-IV [75].

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