6V66
EGFR(T790M/V948R) in complex with LN2899
Summary for 6V66
| Entry DOI | 10.2210/pdb6v66/pdb |
| Descriptor | Epidermal growth factor receptor, CHLORIDE ION, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | egfr, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 151921.51 |
| Authors | Heppner, D.E.,Eck, M.J. (deposition date: 2019-12-04, release date: 2020-04-22, Last modification date: 2024-10-30) |
| Primary citation | Heppner, D.E.,Gunther, M.,Wittlinger, F.,Laufer, S.A.,Eck, M.J. Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors. J.Med.Chem., 63:4293-4305, 2020 Cited by PubMed Abstract: Acquired drug resistance in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer is a persistent challenge in cancer therapy. Previous studies of trisubstituted imidazole inhibitors led to the serendipitous discovery of inhibitors that target the drug resistant EGFR(L858R/T790M/C797S) mutant with nanomolar potencies in a reversible binding mechanism. To dissect the molecular basis for their activity, we determined the binding modes of several trisubstituted imidazole inhibitors in complex with the EGFR kinase domain with X-ray crystallography. These structures reveal that the imidazole core acts as an H-bond acceptor for the catalytic lysine (K745) in the "αC-helix out" inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, noncovalent inhibition of the C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small-cell lung cancer. PubMed: 32243152DOI: 10.1021/acs.jmedchem.0c00200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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