PDBsum entry 3zos

Transferase

PDB id: 3zos

Contents

Protein chains

301 a.a.

Ligands

0LI ×3

EDO ×3

Waters ×336

PDB id:

3zos

Name:

Transferase

Title:

Structure of the ddr1 kinase domain in complex with ponatinib

Structure:

Epithelial discoidin domain-containing receptor 1. Chain: a, b. Fragment: kinase domain, residues 601-913. Synonym: epithelial discoidin domain receptor, cd167 antigen-like family member a, cell adhesion kinase, discoidin receptor tyrosine kinase, hgk2, mammary carcinoma kinase 10, mck-10, protein-tyrosine kinase 3a, protein-tyrosine kinase rtk-6, trk e, tyrosine kinase ddr, tyrosine-protein kinase cak, cd167a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Other_details: mammalian gene collection (mgc)

Resolution:

1.92Å R-factor: 0.208 R-free: 0.234

Authors:

P.Canning,J.M.Elkins,S.Goubin,P.Mahajan,A.Bradley,D.Coutandin,F.Von Delft,C.H.Arrowsmith,A.M.Edwards,C.Bountra,A.Bullock

Key ref:

P.Canning et al. (2014). Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors. J Mol Biol, 426, 2457-2470. PubMed id: 24768818 DOI: 10.1016/j.jmb.2014.04.014

Date:

22-Feb-13 Release date: 01-May-13

Protein chains

Q08345  (DDR1_HUMAN) -  Epithelial discoidin domain-containing receptor 1 from Homo sapiens

Seq: 913 a.a.

Struc: 301 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: 10.1016/j.jmb.2014.04.014

J Mol Biol 426:2457-2470 (2014)

PubMed id: 24768818

Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors.

P.Canning, L.Tan, K.Chu, S.W.Lee, N.S.Gray, A.N.Bullock.

ABSTRACT

The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and αD helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a β-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.