Mechanism of activation and inhibition of the HER4/ErbB4 kinase.
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.
Qiu
Chen
C
Department of Biophysics & Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Tarrant
Mary K
MK
Choi
Sung Hee
SH
Sathyamurthy
Aruna
A
Bose
Ron
R
Banjade
Sudeep
S
Pal
Ashutosh
A
Bornmann
William G
WG
Lemmon
Mark A
MA
Cole
Philip A
PA
Leahy
Daniel J
DJ
D000818:Animals; D002478:Cells, Cultured; D017124:Conserved Sequence; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D000077341:Lapatinib; D008954:Models, Biological; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011799:Quinazolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D066247:Receptor, ErbB-4; D018411:Spodoptera
D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human