Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor α

We report the crystal structure, at 2.5 Å resolution, of a truncated human EGFR ectodomain bound to TGFα. TGFα interacts with both L1 and L2 domains of EGFR, making many main chain contacts with L1 and interacting with L2 via key conserved residues. The results indicate how EGFR family members can b...

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Bibliographic Details
Published in:Cell 2002-09, Vol.110 (6), p.763-773
Main Authors: Garrett, Thomas P.J., McKern, Neil M., Lou, Meizhen, Elleman, Thomas C., Adams, Timothy E., Lovrecz, George O., Zhu, Hong-Jian, Walker, Francesca, Frenkel, Morry J., Hoyne, Peter A., Jorissen, Robert N., Nice, Edouard C., Burgess, Antony W., Ward, Colin W.
Format: Article
Language:English
Subjects:
3T3 Cells
Amino Acid Sequence
Amino Acid Substitution
Animals
Binding Sites
Cell Line
Conserved Sequence
Crystallization
Crystallography, X-Ray
Dimerization
Disulfides - chemistry
ErbB Receptors - chemistry
ErbB Receptors - metabolism
Humans
Ligands
Mice
Models, Molecular
Molecular Sequence Data
Molecular Structure
Mutation
Protein Structure, Secondary
Protein Structure, Tertiary
Sequence Alignment
Transforming Growth Factor alpha - chemistry
Transforming Growth Factor alpha - genetics
Transforming Growth Factor alpha - metabolism
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Summary:We report the crystal structure, at 2.5 Å resolution, of a truncated human EGFR ectodomain bound to TGFα. TGFα interacts with both L1 and L2 domains of EGFR, making many main chain contacts with L1 and interacting with L2 via key conserved residues. The results indicate how EGFR family members can bind a family of highly variable ligands. In the 2:2 TGFα:sEGFR501 complex, each ligand interacts with only one receptor molecule. There are two types of dimers in the asymmetric unit: a head-to-head dimer involving contacts between the L1 and L2 domains and a back-to-back dimer dominated by interactions between the CR1 domains of each receptor. Based on sequence conservation, buried surface area, and mutagenesis experiments, the back-to-back dimer is favored to be biologically relevant.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(02)00940-6