PDBsum entry 4ckr

Transferase

PDB id: 4ckr

Contents

Protein chain

295 a.a.

Ligands

DI1

EDO ×5

Waters ×38

PDB id:

4ckr

Name:

Transferase

Title:

Crystal structure of the human ddr1 kinase domain in complex with ddr1-in-1

Structure:

Epithelial discoidin domain-containing receptor 1. Chain: a. Fragment: kinase domain, residues 601-913. Synonym: epithelial discoidin domain receptor 1, 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:

2.20Å R-factor: 0.201 R-free: 0.247

Authors:

P.Canning,J.M.Elkins,S.Goubin,P.Mahajan,T.Krojer,J.A.Newman,S.Dixon- Clarke,A.Chaikuad,F.Von Delft,C.H.Arrowsmith,A.M.Edwards,C.Bountra, A.Bullock

Key ref:

H.G.Kim et al. (2013). Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor. Acs Chem Biol, 8, 2145-2150. PubMed id: 23899692 DOI: 10.1021/cb400430t

Date:

07-Jan-14 Release date: 15-Jan-14

Supersedes:

4bki

Protein chain

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

Seq: 913 a.a.

Struc: 295 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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/cb400430t

Acs Chem Biol 8:2145-2150 (2013)

PubMed id: 23899692

Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor.

H.G.Kim, L.Tan, E.L.Weisberg, F.Liu, P.Canning, H.G.Choi, S.A.Ezell, H.Wu, Z.Zhao, J.Wang, A.Mandinova, J.D.Griffin, A.N.Bullock, Q.Liu, S.W.Lee, N.S.Gray.

ABSTRACT

The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 Å DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the 'DFG-out' conformation and inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with good selectivity as assessed against a panel of 451 kinases measured using the KinomeScan technology. We identified a mutation in the hinge region of DDR1, G707A, that confers >20-fold resistance to the ability of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to establish what pharmacology is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction.