PMID- 20007378
OWN - NLM
STAT- MEDLINE
DCOM- 20100218
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 106
IP  - 51
DP  - 2009 Dec 22
TI  - Structural analysis of the catalytically inactive kinase domain of the human EGF 
      receptor 3.
PG  - 21608-13
LID - 10.1073/pnas.0912101106 [doi]
AB  - The kinase domain of human epidermal growth factor receptor (HER) 3/ErbB3, a 
      member of the EGF receptor (EGFR) family, lacks several residues that are 
      critical for catalysis. Because catalytic activity in EGFR family members is 
      switched on by an allosteric interaction between kinase domains in an asymmetric 
      kinase domain dimer, HER3 might be specialized to serve as an activator of other 
      EGFR family members. We have determined the crystal structure of the HER3 kinase 
      domain and show that it appears to be locked into an inactive conformation that 
      resembles that of EGFR and HER4. Although the crystal structure shows that the 
      HER3 kinase domain binds ATP, we confirm that it is catalytically inactive but 
      can serve as an activator of the EGFR kinase domain. The HER3 kinase domain forms 
      a dimer in the crystal, mediated by hydrophobic contacts between the N-terminal 
      lobes of the kinase domains. This N-lobe dimer closely resembles a dimer formed 
      by inactive HER4 kinase domains in crystal structures determined previously, and 
      molecular dynamics simulations suggest that the HER3 and HER4 N-lobe dimers are 
      stable. The kinase domains of HER3 and HER4 form similar chains in their 
      respective crystal lattices, in which N-lobe dimers are linked together by 
      reciprocal exchange of C-terminal tails. The conservation of this tiling pattern 
      in HER3 and HER4, which is the closest evolutionary homolog of HER3, might 
      represent a general mechanism by which this branch of the HER receptors restricts 
      ligand-independent formation of active heterodimers with other members of the 
      EGFR family.
FAU - Jura, Natalia
AU  - Jura N
AD  - Department of Molecular and Cell Biology, California Institute for Quantitative 
      Biosciences, University of California, Berkeley, CA 94720, USA.
FAU - Shan, Yibing
AU  - Shan Y
FAU - Cao, Xiaoxian
AU  - Cao X
FAU - Shaw, David E
AU  - Shaw DE
FAU - Kuriyan, John
AU  - Kuriyan J
LA  - eng
SI  - PDB/3KEX
GR  - R01 CA096504/CA/NCI NIH HHS/United States
GR  - R01 CA96504-06/CA/NCI NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20091209
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Allosteric Regulation
MH  - Amino Acid Sequence
MH  - Biocatalysis
MH  - Crystallography, X-Ray
MH  - Dimerization
MH  - ErbB Receptors/*chemistry/metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Dynamics Simulation
MH  - Molecular Sequence Data
MH  - Protein Conformation
MH  - Sequence Homology, Amino Acid
PMC - PMC2791034
COIS- The authors declare no conflict of interest.
EDAT- 2009/12/17 06:00
MHDA- 2010/02/19 06:00
PMCR- 2009/12/09
CRDT- 2009/12/17 06:00
PHST- 2009/12/17 06:00 [entrez]
PHST- 2009/12/17 06:00 [pubmed]
PHST- 2010/02/19 06:00 [medline]
PHST- 2009/12/09 00:00 [pmc-release]
AID - 0912101106 [pii]
AID - 0692 [pii]
AID - 10.1073/pnas.0912101106 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21608-13. doi: 
      10.1073/pnas.0912101106. Epub 2009 Dec 9.