5YU9
Crystal structure of EGFR 696-1022 T790M in complex with Ibrutinib
Summary for 5YU9
| Entry DOI | 10.2210/pdb5yu9/pdb |
| Related | 4YNJ |
| Descriptor | Epidermal growth factor receptor, 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | egfr, t790m, ibrutinib, inhibitor, oncoprotein |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533 |
| Total number of polymer chains | 4 |
| Total formula weight | 152470.74 |
| Authors | |
| Primary citation | Wang, A.,Yan, X.E.,Wu, H.,Wang, W.,Hu, C.,Chen, C.,Zhao, Z.,Zhao, P.,Li, X.,Wang, L.,Wang, B.,Ye, Z.,Wang, J.,Wang, C.,Zhang, W.,Gray, N.S.,Weisberg, E.L.,Chen, L.,Liu, J.,Yun, C.H.,Liu, Q. Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation. Oncotarget, 7:69760-69769, 2016 Cited by PubMed Abstract: Ibrutinib, a clinically approved irreversible BTK kinase inhibitor for Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) etc, has been reported to be potent against EGFR mutant kinase and currently being evaluated in clinic for Non Small Cell Lung Cancer (NSCLC). Through EGFR wt/mutant engineered isogenic BaF3 cell lines we confirmed the irreversible binding mode of Ibrutinib with EGFR wt/mutant kinase via Cys797. However, comparing to typical irreversible EGFR inhibitor, such as WZ4002, the washing-out experiments revealed a much less efficient covalent binding for Ibrutinib. The biochemical binding affinity examination in the EGFR L858R/T790M kinase revealed that, comparing to more efficient irreversible inhibitor WZ4002 (Kd: 0.074 μM), Ibrutinib exhibited less efficient binding (Kd: 0.18 μM). An X-ray crystal structure of EGFR (T790M) in complex with Ibrutinib exhibited a unique DFG-in/c-Helix-out inactive binding conformation, which partially explained the less efficiency of covalent binding and provided insight for further development of highly efficient irreversible binding inhibitor for the EGFR mutant kinase. These results also imply that, unlike the canonical irreversible inhibitor, sustained effective concentration might be required for Ibrutinib in order to achieve the maximal efficacy in the clinic application against EGFR driven NSCLC. PubMed: 27626175DOI: 10.18632/oncotarget.11951 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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