7TM domain structures of adhesion GPCRs: what's new and what's missing?

Adhesion-type G protein-coupled receptors (aGPCRs) have long resisted ap-proach es to resolve the structural details of their heptahelical transmembrane (7TM) domains. Single-particle cryogenic electron microscopy (cryo-EM) has re-cently produced aGPCR 7TM domain structures for ADGRD1, ADGRG1, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRF1, and ADGRL3. We review the unique properties, including the position and conformation of their activating tethered agonist (TA) and signaling motifs within the 7TM bundle, that the novel structures have helped to identify. We also discuss questions that the kaleido-scope of novel aGPCR 7TM domain structures have left unanswered. These con-cern the relative positions, orientations, and interactions of the 7TM and GPCR autoproteolysis-inducing (GAIN) domains with one another. Clarifying their inter-play remains an important goal of future structural studies on aGPCRs.