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PMID: 18334220 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Mechanism of activation and inhibition of the HER4/ErbB4 kinase.

Structure (London, England : 1993) ·Vol. 16 ·No. 3 ·2008-03-00 ·Pages 460-7

Qiu C, Tarrant MK, Choi SH, Sathyamurthy A, Bose R, Banjade S, Pal A, Bornmann WG, Lemmon MA, Cole PA, Leahy DJ

Abstract

HER4/ErbB4 is a ubiquitously expressed member of the EGF/ErbB family of receptor tyrosine kinases that is essential for normal development of the heart, nervous system, and mammary gland. We report here crystal structures of the ErbB4 kinase domain in active and lapatinib-inhibited forms. Active ErbB4 kinase adopts an asymmetric dimer conformation essentially identical to that observed to be important for activation of the EGF receptor/ErbB1 kinase. Mutagenesis studies of intact ErbB4 in Ba/F3 cells confirm the importance of this asymmetric dimer for activation of intact ErbB4. Lapatinib binds to an inactive form of the ErbB4 kinase in a mode equivalent to its interaction with the EGF receptor. All ErbB4 residues contacted by lapatinib are conserved in the EGF receptor and HER2/ErbB2, which lapatinib also targets. These results demonstrate that key elements of kinase activation and inhibition are conserved among ErbB family members.

MeSH Terms
Animals Cells, Cultured Conserved Sequence Enzyme Activation/drug effects ErbB Receptors/antagonists & inhibitors,chemistry,metabolism Humans Lapatinib Models, Biological Models, Molecular Protein Binding Protein Kinase Inhibitors/chemistry,metabolism,pharmacology Protein Structure, Quaternary Protein Structure, Secondary Quinazolines/chemistry,metabolism,pharmacology Receptor, ErbB-2/chemistry,metabolism Receptor, ErbB-4 Spodoptera
Chemicals
Protein Kinase Inhibitors Quinazolines Lapatinib ERBB2 protein, human ERBB4 protein, human ErbB Receptors Receptor, ErbB-2 Receptor, ErbB-4
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Qiu Chen
Department of Biophysics & Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Tarrant Mary K
Choi Sung Hee
Sathyamurthy Aruna
Bose Ron
Banjade Sudeep
Pal Ashutosh
Bornmann William G
Lemmon Mark A
Cole Philip A
Leahy Daniel J
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Article Info
Journal
Structure (London, England : 1993)
Abbr.
Structure
ISSN
0969-2126
DOI
10.1016/j.str.2007.12.016
Published
2008-03-00
Pages
460-7
Language
English
Region
United States
NLM ID
101087697
PMCID
PMC2858219
Subset
IM
Grants
NCI NIH HHS · R01-CA74305 · United States
NCI NIH HHS · R01 CA079992 · United States
NCI NIH HHS · R01-CA90466 · United States
NCI NIH HHS · R01 CA090466-08 · United States
NCI NIH HHS · R01 CA090466 · United States
NCI NIH HHS · R01 CA079992-12 · United States
NCI NIH HHS · R01 CA074305-15 · United States
NCI NIH HHS · R01-CA079992 · United States
NIGMS NIH HHS · R01 GM099321 · United States
NCI NIH HHS · R01 CA074305 · United States
Databases
PDB
3BBT, 3BBW, 3BCE
Corrections
CommentIn
PMID: 18334205
External Links
PubMed source DOI: 10.1016/j.str.2007.12.016 PMC Full Text View journal details
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