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.