(A) Profile of a vesicle (pale blue) docked on the presynaptic membrane (gray) viewed in the transverse plane of the active zone. AZM macromolecules, including a rib (gold), a spar (red), a boom (purple) and a pin (copper), connect to the outer surface of the vesicle membrane as do non-AZM macromolecules (pewter). The luminal assembly of macromolecules is orange. Nubs arise from the luminal assembly’s arms to connect to the vesicle membrane, where they are linked to macromolecules that span the membrane (dark blue) and connect to the AZM and non-AZM macromolecules. (B) Profile of a docked vesicle viewed from the active zone’s median plane. The arms of the luminal assembly radiate from a point near the center of the vesicle and are larger near the vesicle membrane than at the vesicle’s center. The arms in the hemisphere facing the presynaptic membrane are shorter than those away from the presynaptic membrane. Colored spots on the luminal assembly mark regions connected by nubs and their membrane spanning macromolecules to specific classes of AZM and non-AZM macromolecules, as in (A). C) 3D arrangement of docked and nearby undocked vesicles relative to the AZM and presynaptic membrane. The orientation of the stereotypic shape of the luminal assembly with respect to the median plane of the AZM and presynaptic membrane is indicated by 3D arrows. The orientation is the same for docked vesicles (red arrows) while for undocked vesicles (blue arrows) it is not. Thus, in order for an undocked vesicle to replace a docked vesicle that fuses with the presynaptic membrane during synaptic transmission, it must, typically, rotate so the appropriate vesicle membrane macromolecules linked to the luminal assembly (A,B) can sequentially interact with the different classes of AZM macromolecules that direct it to the docking site on the presynaptic membrane.