title: Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation.
abstract: Overexpression of the epidermal growth factor (EGF) receptor (EGFR) in cancer cells correlates with tumor malignancy and poor prognosis for cancer patients. For this reason, the EGFR has become one of the main targets of anticancer therapies. Structural data obtained in the last few years have revealed the molecular mechanism for ligand-induced EGFR dimerization and subsequent signal transduction, and also how this signal is blocked by either monoclonal antibodies or small molecules. Nimotuzumab (also known as h-R3) is a humanized antibody that targets the EGFR and has been successful in the clinics. In this work, we report the crystal structure of the Fab fragment of Nimotuzumab, revealing some unique structural features in the heavy variable domain. Furthermore, competition assays show that Nimotuzumab binds to domain III of the extracellular region of the EGFR, within an area that overlaps with both the surface patch recognized by Cetuximab (another anti-EGFR antibody) and the binding site for EGF. A computer model of the Nimotuzumab-EGFR complex, constructed by docking and molecular dynamics simulations and supported by mutagenesis studies, unveils a novel mechanism of action, with Nimotuzumab blocking EGF binding while still allowing the receptor to adopt its active conformation, hence warranting a basal level of signaling.
authors: Center of Molecular Immunology, Havana, Cuba.
authors: Ariel
authors: A
authors: Talavera
authors: Rosmarie
authors: R
authors: Friemann
authors: Silvia
authors: S
authors: Gómez-Puerta
authors: Carlos
authors: C
authors: Martinez-Fleites
authors: Greta
authors: G
authors: Garrido
authors: Ailem
authors: A
authors: Rabasa
authors: Alejandro
authors: A
authors: López-Requena
authors: Amaury
authors: A
authors: Pupo
authors: Rune F
authors: RF
authors: Johansen
authors: Oliberto
authors: O
authors: Sánchez
authors: Ute
authors: U
authors: Krengel
authors: Ernesto
authors: E
authors: Moreno
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D011993:Recombinant Fusion Proteins; C501466:nimotuzumab; D066246:ErbB Receptors