Communication across the neuromuscular junction can be compromised in several ways, leading to debilitating disorders involving muscular weakness and fatigue. For example, in the auto-immune disease Myasthenia gravis, antibodies bind to, and cross-link neighbouring ACh receptors causing a reduction in their number. Most of these antibodies bind to a particular location - the Main Immunogenic Region (MIR)
Cryo-electron crystallographic studies of the receptor complexed with fragments of an MIR-directed antibody show that this location is at the extreme extracellular end (i.e. opposite to the end where the clustering protein rapsyn binds). The site and orientation of the attachment are such that the antibody does not have to insert between the densely packed receptors to interact with them. Avoidance of steric hindrance by this means would ensure efficient removal of receptors, producing ultimately the symptoms of the disease.
Beroukhim, R. and Unwin, N. Three-dimensional location of the main-immunogenic region of the acetylcholine receptor. Neuron 15, 323-331 (1995). (pdf)