Cryo-EM structures of the ionotropic glutamate receptor GluD1 reveal a non- swapped architecture, A.P. Burada (a),
R. Vinnakota (a) and J. Kumar (a), Nat. Struct. Mol. Biol. 27, 84-91 (2020); https:// doi.org/10.1038/s41594-019-0359-y.
(a) Laboratory of Membrane Protein Biology, National Centre for Cell Science, S.P. Pune University, Maharashtra (India)
 M. Yuzaki & A.R. Aricescu, Trends Neurosci. 40, 138-150 (2017).  I.H. Greger & L.M. Mayer, Curr. Opin. Struct. Biol. 57, 185-195 (2019).  A.P. Burada et al., J. Struct. Biol. 211, 107546 (2020).
PRINCIPAL PUBLICATION AND AUTHORS
Due to this, multiple conformations of GluD1 were observed in the samples (Figure 42). The structure also highlighted other important features distinguishing GluD1 receptors from AMPA and kainate receptors, such as ATD and LBD arrangement in the same vertical plane and reduced tetramerisation interface at the ATD layer, unlike that in AMPA and Kainate. Furthermore, a shorter loop connecting ATD and LBD, coupled with a large interaction interface at both these domains, leads to the packing of ATD and LBD closer to each other than observed in AMPA and Kainate receptors. In turn, this domain placement results in ATD and LBD packing on top of each other in a linear fashion.
In addition to the extracellular domains, the transmembrane (TM) domain arrangement is also unique in GluD1 when compared with other iGluRs. While the four-fold rotational symmetry is conserved, the subunits are arranged as A-B-C-D in a counter-clockwise manner. In contrast, the TM domains are placed in a clockwise arrangement in other iGluRs (Figure 43). However, as observed in other iGluRs, the pre-M1 cuff helix lies parallel to the plane of the membrane, with the M3 helix from four subunits lining the pore together with the re-entrant M2 loop. Yet, unlike AMPA and Kainate receptors, the TM assembly seems to be more expanded, as observed in NMDA receptors.
As an overview, the enigmatic GluD1 receptor structure, along with the recently reported GluD2 structure , demonstrates that principles of architecture and symmetry are not conserved between delta receptors and other iGluRs. This work also corrects the model for the trans- synaptic complex formed between presynaptic neurexin and GluD receptors mediated by cerebelins. Thus, this study provides molecular
Fig. 43: The non-swapped domain architecture observed in GluD1. a) Top views of the ATD, LBD and TM domains and their cartoon
depictions for (a) GluA2 (PDB ID: 4U4G) and (b) GluD1 (PDB ID: 6KSS) are shown. The square box in panel (a) for GluA2 shows the swapping of dimer partners at the LBD domain layer, which is not seen in GluD1. The
differences in the arrangement of TM domains are also highlighted.
blueprints for understanding the functions of GluD receptors and leads the way towards a mechanistic understanding of GluD1 receptor signalling at CNS synapses.