PDBsum entry 5bvw

Transferase

PDB id: 5bvw

Contents

Protein chain

274 a.a.

Ligands

1N1

Metals

IOD ×8

Waters ×287

PDB id:

5bvw

Name:

Transferase

Title:

Fragment-based discovery of potent and selective ddr1/2 inhibitors

Structure:

Epithelial discoidin domain-containing receptor 1. Chain: a. Fragment: resideus 576-894. 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. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ddr1, cak, eddr1, nep, ntrk4, ptk3a, rtk6, trke. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.94Å R-factor: 0.186 R-free: 0.234

Authors:

C.Murray,V.Berdini,I.Buck,M.Carr,A.Cleasby,J.Coyle,J.Curry,J.Day, K.Hearn,A.Iqbal,L.Lee,V.Martins,P.Mortenson,J.Munck,L.Page,S.Patel, S.Roomans,T.Kirsten,G.Saxty

Key ref:

C.W.Murray et al. (2015). Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors. Acs Med Chem Lett, 6, 798-803. PubMed id: 26191369 DOI: 10.1021/acsmedchemlett.5b00143

Date:

05-Jun-15 Release date: 05-Aug-15

Protein chain

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

Seq: 913 a.a.

Struc: 274 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/acsmedchemlett.5b00143

Acs Med Chem Lett 6:798-803 (2015)

PubMed id: 26191369

Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.

C.W.Murray, V.Berdini, I.M.Buck, M.E.Carr, A.Cleasby, J.E.Coyle, J.E.Curry, J.E.Day, P.J.Day, K.Hearn, A.Iqbal, L.Y.Lee, V.Martins, P.N.Mortenson, J.M.Munck, L.W.Page, S.Patel, S.Roomans, K.Smith, E.Tamanini, G.Saxty.

ABSTRACT

The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.