6JX4

Crystal structure of EGFR 696-1022 T790M in complex with AZD9291 prepared by soaking

Summary for 6JX4

• Entry DOI: 10.2210/pdb6jx4/pdb
• Related: 6JWL 6JX0
• Descriptor: Epidermal growth factor receptor, N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide (3 entities in total)
• Functional Keywords: complex, inhibitor, egfr., oncoprotein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 38150.21

Authors

Zhu, S.J.,Yan, X.E.,Yun, C.H. (deposition date: 2019-04-22, release date: 2020-04-22, Last modification date: 2020-11-04)

Primary citation

Yan, X.E.,Ayaz, P.,Zhu, S.J.,Zhao, P.,Liang, L.,Zhang, C.H.,Wu, Y.C.,Li, J.L.,Choi, H.G.,Huang, X.,Shan, Y.,Shaw, D.E.,Yun, C.H.
Structural Basis of AZD9291 Selectivity for EGFR T790M.
J.Med.Chem., 63:8502-8511, 2020

PubMed Abstract: AZD9291 (Osimertinib) is highly effective in treating EGFR-mutated non-small-cell lung cancers (NSCLCs) with T790M-mediated drug resistance. Despite the remarkable success of AZD9291, its binding pose with EGFR T790M remains unclear. Here, we report unbiased, atomic-level molecular dynamics (MD) simulations in which spontaneous association of AZD9291 with EGFR kinases having WT and T790M mutant gatekeepers was observed. Simulation-generated structural models suggest that the binding pose of AZD9291 with T790M differs from its binding pose with the WT, and that AZD9291 interacts extensively with the gatekeeper residue (Met 790) in T790M but not with Thr 790 in the WT, which explains why AZD9291 binds T790M with higher affinity. The MD simulation-generated models were confirmed by experimentally determined EGFR/T790M complex crystal structures. This work may facilitate the rational design of drugs that can overcome resistance mutations to AZD9291, and more generally it suggests the potential of using unbiased MD simulation to elucidate small-molecule binding poses.

PubMed: 32672461
DOI: 10.1021/acs.jmedchem.0c00891

Experimental method

X-RAY DIFFRACTION (2.531 Å)