7SZ0
Cryo-EM structure of the extracellular module of the full-length EGFR L834R bound to EGF. "tips-juxtaposed" conformation
Summary for 7SZ0
| Entry DOI | 10.2210/pdb7sz0/pdb |
| EMDB information | 25558 |
| Descriptor | Epidermal growth factor receptor, Epidermal growth factor (2 entities in total) |
| Functional Keywords | receptor tyrosine kinases, epidermal growth factor receptor, signaling protein, signaling protein-receptor complex, signaling protein/receptor |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 281412.80 |
| Authors | Huang, Y.,Ognjenovic, J.,Karandur, D.,Miller, K.,Merk, A.,Subramaniam, S.,Kuriyan, J. (deposition date: 2021-11-25, release date: 2021-12-22) |
| Primary citation | Huang, Y.,Ognjenovic, J.,Karandur, D.,Miller, K.,Merk, A.,Subramaniam, S.,Kuriyan, J. A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor. Elife, 10:-, 2021 Cited by PubMed Abstract: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family. PubMed: 34846302DOI: 10.7554/eLife.73218 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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