PDBsum entry 4jrv

Transferase/transferase inhibitor

PDB id: 4jrv

Contents

Protein chain

300 a.a.

Ligands

KJV

Waters ×21

PDB id:

4jrv

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of egfr kinase domain in complex with compound 4c

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: egfr kinase domain, unp residues 696-1021. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein kinase erbb-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: hi5.

Resolution:

2.80Å R-factor: 0.194 R-free: 0.227

Authors:

Y.H.Peng,J.S.Wu

Key ref:

Y.H.Peng et al. (2013). 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. PubMed id: 23611691 DOI: 10.1021/jm400072p

Date:

22-Mar-13 Release date: 19-Jun-13

Protein chain

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 300 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jm400072p

J Med Chem 56:3889-3903 (2013)

PubMed id: 23611691

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.

Y.H.Peng, H.Y.Shiao, C.H.Tu, P.M.Liu, J.T.Hsu, P.K.Amancha, J.S.Wu, M.S.Coumar, C.H.Chen, S.Y.Wang, W.H.Lin, H.Y.Sun, Y.S.Chao, P.C.Lyu, H.P.Hsieh, S.Y.Wu.

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.