4JQ7

Crystal structure of EGFR kinase domain in complex with compound 2a

Summary for 4JQ7

• Entry DOI: 10.2210/pdb4jq7/pdb
• Descriptor: Epidermal growth factor receptor, (2S)-2-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]-2-phenylethanol (3 entities in total)
• Functional Keywords: transferase, tyrosine kinase domain, atp-binding domain, autophosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 37808.71

Authors

Peng, Y.H.,Wu, J.S. (deposition date: 2013-03-20, release date: 2013-06-19, Last modification date: 2023-11-08)

Primary citation

Peng, Y.H.,Shiao, H.Y.,Tu, C.H.,Liu, P.M.,Hsu, J.T.,Amancha, P.K.,Wu, J.S.,Coumar, M.S.,Chen, C.H.,Wang, S.Y.,Lin, W.H.,Sun, H.Y.,Chao, Y.S.,Lyu, P.C.,Hsieh, H.P.,Wu, S.Y.
Protein Kinase Inhibitor Design by Targeting the Asp-Phe-Gly (DFG) Motif: The Role of the DFG Motif in the Design of Epidermal Growth Factor Receptor Inhibitors
J.Med.Chem., 56:3889-3903, 2013

PubMed Abstract: The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.

PubMed: 23611691
DOI: 10.1021/jm400072p

Experimental method

X-RAY DIFFRACTION (2.73 Å)