2J5F

Crystal structure of EGFR kinase domain in complex with an irreversible inhibitor 34-jab

Summary for 2J5F

• Entry DOI: 10.2210/pdb2j5f/pdb
• Related: 1DNQ 1DNR 1IVO 1M14 1M17 1MOX 1NQL 1XKK 1YY9 1Z9I 2GS2 2GS7 2ITN 2ITO 2ITP 2ITQ 2ITT 2ITU 2ITV 2ITW 2ITX 2ITY 2ITZ 2J5E
• Descriptor: EPIDERMAL GROWTH FACTOR RECEPTOR, N-[4-(3-BROMO-PHENYLAMINO)-QUINAZOLIN-6-YL]-ACRYLAMIDE (3 entities in total)
• Functional Keywords: cell cycle, atp-binding, transferase, polymorphism, irreversible inhibitor, tyrosine-protein kinase, egfr, kinase, 34-jab, membrane, receptor, wild-type, epidermal growth factor, anti-oncogene, transmembrane, nucleotide-binding, alternative splicing, ubl conjugation, phosphorylation, disease mutation, glycoprotein
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 37673.34

Authors

Yun, C.-H.,Eck, M.J. (deposition date: 2006-09-14, release date: 2007-02-27, Last modification date: 2024-11-13)

Primary citation

Blair, J.A.,Rauh, D.,Kung, C.,Yun, C.-H.,Fan, Q.-W.,Rode, H.,Zhang, C.,Eck, M.J.,Weiss, W.A.,Shokat, K.M.
Structure-Guided Development of Affinity Probes for Tyrosine Kinases Using Chemical Genetics.
Nat.Chem.Biol., 3:229-, 2007

PubMed Abstract: As key components in nearly every signal transduction pathway, protein kinases are attractive targets for the regulation of cellular signaling by small-molecule inhibitors. We report the structure-guided development of 6-acrylamido-4-anilinoquinazoline irreversible kinase inhibitors that potently and selectively target rationally designed kinases bearing two selectivity elements that are not found together in any wild-type kinase: an electrophile-targeted cysteine residue and a glycine gatekeeper residue. Cocrystal structures of two irreversible quinazoline inhibitors bound to either epidermal growth factor receptor (EGFR) or engineered c-Src show covalent inhibitor binding to the targeted cysteine (Cys797 in EGFR and Cys345 in engineered c-Src). To accommodate the new covalent bond, the quinazoline core adopts positions that are different from those seen in kinase structures with reversible quinazoline inhibitors. Based on these structures, we developed a fluorescent 6-acrylamido-4-anilinoquinazoline affinity probe to report the fraction of kinase necessary for cellular signaling, and we used these reagents to quantitate the relationship between EGFR stimulation by EGF and its downstream outputs-Akt, Erk1 and Erk2.

PubMed: 17334377
DOI: 10.1038/NCHEMBIO866

Experimental method

X-RAY DIFFRACTION (3 Å)