PMID- 12011054 OWN - NLM STAT- MEDLINE DCOM- 20020916 LR - 20210206 IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 277 IP - 31 DP - 2002 Aug 2 TI - Disabling receptor ensembles with rationally designed interface peptidomimetics. PG - 28330-9 AB - 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. FAU - Berezov, Alan AU - Berezov A AD - Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine and the Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania 19104, USA. FAU - Chen, Jinqiu AU - Chen J FAU - Liu, Qingdu AU - Liu Q FAU - Zhang, Hong-Tao AU - Zhang HT FAU - Greene, Mark I AU - Greene MI FAU - Murali, Ramachandran AU - Murali R LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20020514 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Peptide Fragments) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.10.1 (Receptor, ErbB-3) SB - IM MH - Amino Acid Sequence MH - Dimerization MH - Drug Design MH - ErbB Receptors/chemistry/metabolism MH - Humans MH - Kinetics MH - Models, Molecular MH - Molecular Sequence Data MH - Peptide Fragments/*chemical synthesis/chemistry/*metabolism MH - Protein Conformation MH - Receptor, ErbB-2/chemistry/metabolism MH - Receptor, ErbB-3/chemistry/metabolism EDAT- 2002/05/16 10:00 MHDA- 2002/09/17 10:01 CRDT- 2002/05/16 10:00 PHST- 2002/05/16 10:00 [pubmed] PHST- 2002/09/17 10:01 [medline] PHST- 2002/05/16 10:00 [entrez] AID - S0021-9258(19)66306-4 [pii] AID - 10.1074/jbc.M202880200 [doi] PST - ppublish SO - J Biol Chem. 2002 Aug 2;277(31):28330-9. doi: 10.1074/jbc.M202880200. Epub 2002 May 14.