7TVD

Crystal structure of the kinase domain of EGFR exon-19 (del-747-749) mutant

Summary for 7TVD

• Entry DOI: 10.2210/pdb7tvd/pdb
• Descriptor: Epidermal growth factor receptor (1 entity in total)
• Functional Keywords: egfr, exon-19, kinase, oncoprotein, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38237.19

Authors

Ashtekar, K.D.,Stayrook, S.E.,Lemmon, M.A. (deposition date: 2022-02-04, release date: 2022-02-16, Last modification date: 2023-10-25)

Primary citation

van Alderwerelt van Rosenburgh, I.K.,Lu, D.M.,Grant, M.J.,Stayrook, S.E.,Phadke, M.,Walther, Z.,Goldberg, S.B.,Politi, K.,Lemmon, M.A.,Ashtekar, K.D.,Tsutsui, Y.
Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations.
Nat Commun, 13:6791-6791, 2022

PubMed Abstract: Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. Using purified TKDs, we compared kinetic properties of several exon 19 variants. Although unaltered for the second generation TKI afatinib, sensitivity varied significantly for both the first and third generation TKIs erlotinib and osimertinib. The most sensitive variants showed reduced ATP-binding affinity, whereas those associated with primary resistance retained wild type ATP-binding characteristics (and low K). Through crystallographic and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies, we identify possible origins for the altered ATP-binding affinity underlying TKI sensitivity and resistance, and propose a basis for classifying uncommon exon 19 variants that may have predictive clinical value.

PubMed: 36357385
DOI: 10.1038/s41467-022-34398-z

Experimental method

X-RAY DIFFRACTION (2.96 Å)