4I21

Crystal structure of L858R + T790M EGFR kinase domain in complex with MIG6 peptide

Summary for 4I21

• Entry DOI: 10.2210/pdb4i21/pdb
• Related: 4I1Z 4I20 4I22 4I23 4I24
• Descriptor: Epidermal growth factor receptor, ERBB receptor feedback inhibitor 1 (2 entities in total)
• Functional Keywords: egfr kinase domain, phosphotransfer, mig6 peptide, atp binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533; Cytoplasm : Q9UJM3
• Total number of polymer chains: 4
• Total formula weight: 88243.49

Authors

Gajiwala, K.S.,Feng, J.,Ferre, R.,Ryan, K.,Brodsky, O.,Stewart, A. (deposition date: 2012-11-21, release date: 2013-01-16, Last modification date: 2024-02-28)

Primary citation

Gajiwala, K.S.,Feng, J.,Ferre, R.,Ryan, K.,Brodsky, O.,Weinrich, S.,Kath, J.C.,Stewart, A.
Insights into the Aberrant Activity of Mutant EGFR Kinase Domain and Drug Recognition.
Structure, 21:209-219, 2013

PubMed Abstract: The oncogenicity of the L858R mutant form of the epidermal growth factor receptor (EGFR) in non-small-cell lung cancer is thought to be due to the constitutive activation of its kinase domain. The selectivity of the marketed drugs gefitinib and erlotinib for L858R mutant is attributed to their specific recognition of the active kinase and to weaker ATP binding by L858R EGFR. We present crystal structures showing that neither L858R nor the drug-resistant L858R+T790M EGFR kinase domain is in the constitutively active conformation. Additional co-crystal structures show that gefitinib and dacomitinib, an irreversible anilinoquinazoline derivative currently in clinical development, may not be conformation specific for the active state of the enzyme. Structural data further reveal the potential mode of recognition of one of the autophosphorylation sites in the C-terminal tail, Tyr-1016, by the kinase domain. Biochemical and biophysical evidence suggest that the oncogenic mutations impact the conformational dynamics of the enzyme.

PubMed: 23273428
DOI: 10.1016/j.str.2012.11.014

Experimental method

X-RAY DIFFRACTION (3.37 Å)