title: Disabling receptor ensembles with rationally designed interface peptidomimetics.
abstract: Members of the erbB family receptor tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in a variety of human cancers and represent important targets for the structure-based drug design. Homo- and heterodimerization (oligomerization) of the erbB receptors are known to be critical events for receptor signaling. To block receptor self-associations, we have designed a series of peptides derived from potential dimerization surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides). In surface plasmon resonance (BIAcore) studies, the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin-induced interactions of erbB3 with different erbB receptors. A dose-dependent inhibition of native erbB receptor dimerization by the erbB peptides has been observed in 32D cell lines transfected with different combinations of erbB receptors. The peptides effectively inhibited growth of two types of transformed cells overexpressing different erbB receptors, T6-17 and 32D, in standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and cell viability assays. The study identifies distinct loops within the membrane-proximal part of the subdomain IV as potential receptor-receptor interaction sites for the erbB receptors and demonstrates the possibility of disabling receptor activity by structure-based targeting of the dimerization interfaces. Molecular models for possible arrangement of the erbB1.EGF complex, consistent with the involvement of subdomain IV in inter-receptor interactions, are proposed. Small dimerization inhibitors described herein can be useful as probes to elucidate different erbB signaling pathways and may be developed as therapeutic agents.
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and the Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania 19104, USA.
authors: Alan
authors: A
authors: Berezov
authors: Jinqiu
authors: J
authors: Chen
authors: Qingdu
authors: Q
authors: Liu
authors: Hong-Tao
authors: HT
authors: Zhang
authors: Mark I
authors: MI
authors: Greene
authors: Ramachandran
authors: R
authors: Murali
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D015195:Drug Design; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3