PDBsum entry 6bsd

Transferase/transferase inhibitor

PDB id: 6bsd

Contents

Protein chain

278 a.a.

Ligands

1N1

Waters ×61

PDB id:

6bsd

Name:

Transferase/transferase inhibitor

Title:

Ddr1 bound to dasatinib

Structure:

Epithelial discoidin domain-containing receptor 1. Chain: a. Fragment: protein kinase domain, residues 526-876. 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. Expression_system_cell_line: sf9. Expression_system_atcc_number: crl-1711

Resolution:

2.61Å R-factor: 0.186 R-free: 0.255

Authors:

G.Georghiou,M.A.Seeliger

Key ref:

S.M.Hanson et al. (2019). What Makes a Kinase Promiscuous for Inhibitors? Cell Chem Biol, 26, 390. PubMed id: 30612951 DOI: 10.1016/j.chembiol.2018.11.005

Date:

02-Dec-17 Release date: 05-Dec-18

Protein chain

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

Seq: 913 a.a.

Struc: 278 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.chembiol.2018.11.005

Cell Chem Biol 26:390 (2019)

PubMed id: 30612951

What Makes a Kinase Promiscuous for Inhibitors?

S.M.Hanson, G.Georghiou, M.K.Thakur, W.T.Miller, J.S.Rest, J.D.Chodera, M.A.Seeliger.

ABSTRACT

ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through clustering analysis of a large kinome profiling dataset, we found a cluster of eight promiscuous kinases that on average bind more than five times more kinase inhibitors than the other 398 kinases in the dataset. To understand the structural basis of promiscuous inhibitor binding, we determined the co-crystal structure of the receptor tyrosine kinase DDR1 with the type I inhibitors dasatinib and VX-680. Surprisingly, we find that DDR1 binds these type I inhibitors in an inactive conformation typically reserved for type II inhibitors. Our computational and biochemical studies show that DDR1 is unusually stable in this inactive conformation, giving a mechanistic explanation for inhibitor promiscuity. This phenotypic clustering analysis provides a strategy to obtain functional insights not available by sequence comparison alone.