Partial agonism and antagonism of the ionotropic glutamate receptor iGLuR5 - Structures of the ligand-binding core in complex with domoic acid and 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid

More than 50 structures have been reported on the ligandbinding core of the ionotropic glutamate receptor iGluR2 that belongs to the 2-amino- 3-(3- hydroxy-5-methyl-4-isoxazolyl) propionic acid-type of receptors. In contrast, the ligand-binding core of the kainic acid-type receptor iGluR5 has only been crystallized with three different ligands. Hence, additional structures of iGluR5 are needed to broaden the understanding of the ligand-binding properties of iGluR5, and the conformational changes leading to channel opening and closing. Here, we present two structures of the ligandbinding core of iGluR5; one as a complex with the partial agonist (2S, 3S, 4S)-3-carboxymethyl- 4-[(1Z, 3E, 5R)-5-carboxy-1methyl- hexa-1,3-dienyl]- pyrrolidine- 2-carboxylic acid ( domoic acid) and one as a complex with the antagonist ( S)- 2-amino- 3[ 5-tert-butyl-3-( phosphonomethoxy)- 4- isoxazolyl] propionic acid (( S)- ATPO). In agreement with the partial agonist activity of domoic acid, the ligand-binding core of the iGluR5 complex is stabilized by domoic acid in a conformation that is 11 more open than the conformation observed in the full agonist ( S)glutamic acid complex. This is primarily caused by the 5-carboxy1- methyl-hexa-1,3- dienyl moiety of domoic acid and residues Val(685)-Thr(690) of iGluR5. An even larger domain opening of 28 is introduced upon binding of the antagonist ( S)- ATPO. It appears that the span of domain opening is much larger in the ligand-binding core of iGluR5 ( 30) compared with what has been observed in iGluR2 ( 19). Similarly, much larger variation in the distances between transmembrane linker residues in the two protomers comprising the dimer is observed in iGluR5 as compared with iGluR2.