Magic bullets from llamas

Abstract

Monoclonal antibodies are effective therapies for many disorders, but their nature and use continues to evolve as technologies emerge to improve their drug-like qualities. In this issue of Structure, Schmitz and colleagues report on structural and biophysical characterizations of single-domain "nanobodies" from llamas that target the epidermal growth factor receptor by both old and new mechanisms.

Figure 1

Activation and inhibition of EGFR extracellular regions. A) The EGFR extracellular region is composed of 4 subdomains: I (blue), II (green), III (yellow), and IV (red). In the absence of ligand a loop from domain II contacts a pocket in domain IV and maintains EGFR in a tethered conformation in which ligand binding surfaces on domains I and III are too far apart to contact ligand simultaneously. Ligand binding stabilizes a domain rearrangement that exposes the domain II loop, which mediates receptor dimerization and conversion to a signaling-competent state. B) Cetuximab and the nanobody 7D12 bind to the EGFR ligand binding site, competing for ligand binding and sterically blocking the extended conformation of the active dimer. The nanobodies EgA1 and 9G8 bind at the hinge region between domains II and III and preclude conversion to the extended conformation without competing for ligand binding.