期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：43
页码：13225-13230
DOI：10.1073/pnas.1518361112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMany cancers are driven by aberrant activation of members of the EGF receptor (EGFR) family including ErbB2 (HER2) and ErbB3 (HER3). EGFR and ErbB3 exist in equilibrium between a tethered, inactive conformation and an extended, active state poised toward formation of homo- or heterodimers with other members of the EGFR family, normally in a ligand-dependent manner. In cancers, these receptors are activated by aberrant ligand stimulation or via a ligand-independent mechanism. Here we describe the crystal structure of the extracellular domain of ErbB3 in complex with a therapeutic antibody, revealing a unique allosteric mechanism for inhibition of cancer cells by locking ErbB3 in the autoinhibited configuration. This mechanism offers new therapeutic opportunities for treating cancers driven by aberrant EGFR, ErbB2, or ErbB3 activation. ErbB3 (HER3) is a member of the EGF receptor (EGFR) family of receptor tyrosine kinases, which, unlike the other three family members, contains a pseudo kinase in place of a tyrosine kinase domain. In cancer, ErbB3 activation is driven by a ligand-dependent mechanism through the formation of heterodimers with EGFR, ErbB2, or ErbB4 or via a ligand-independent process through heterodimerization with ErbB2 overexpressed in breast tumors or other cancers. Here we describe the crystal structure of the Fab fragment of an antagonistic monoclonal antibody KTN3379, currently in clinical development in human cancer patients, in complex with the ErbB3 extracellular domain. The structure reveals a unique allosteric mechanism for inhibition of ligand-dependent or ligand-independent ErbB3-driven cancers by binding to an epitope that locks ErbB3 in an inactive conformation. Given the similarities in the mechanism of ErbB receptor family activation, these findings could facilitate structure-based design of antibodies that inhibit EGFR and ErbB4 by an allosteric mechanism.
