Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3
Open accessAbstract
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.
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The mutation may interfere with an adjacent electrostatic switch interaction proposed to stabilize an inactive EGFR dimer.
“This mutation may also interfere with an adjacent “electrostatic switch” interaction that is proposed to stabilize an inactive EGFR dimer 49.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [49]
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- Authors
- Jura, N., Shan, Y., Cao, X., Shaw, D. E., & Kuriyan, J.
- Affiliations
- QB3 (US)
- D. E. Shaw Research (US)
- Corresponding author
- Kuriyan, John
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-12-22
- Volume
- 106
- Issue
- 51
- Pages
- 21608-21613
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2791034
- OpenAlex
- W1978343870
- Cited by
- 338
- References
- 40
- Citations by year
- 2026: 15 · 2025: 11 · 2024: 14 · 2023: 8 · 2022: 19 · 2021: 17 · 2020: 29 · 2019: 14 · 2018: 18 · 2017: 20 · 2016: 27 · 2015: 24 · 2014: 30 · 2013: 33 · 2012: 24
- FWCI
- 10.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Energy (DE-AC03-?, AC03-76SF00098, DEAC03-76SF00098, Contract DE-AC03-76SF00098)
- Susan G. Komen for the Cure
- National Cancer Institute (CA96504, R01CA096504, R01 CA96504-06)
- Lawrence Berkeley National Laboratory (DE AC03 76SF00098)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- HER3, EGF receptor family, kinase domain, crystal structure, catalytic inactivity, allosteric activation, ErbB4, ATP binding, heterodimer formation, ligand-independent receptor activation, molecular dynamics simulation
- MeSH terms
- Allosteric Regulation, Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Protein Conformation, Sequence Homology, Amino Acid, Crystallography, X-Ray, Dimerization, Biocatalysis, Molecular Dynamics Simulation, ErbB Receptors
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