PDBsum entry 2x2m

Transferase

PDB id: 2x2m

Contents

Protein chain

287 a.a. *

Ligands

FMT ×5

X2M ×2

Waters ×45

* Residue conservation analysis

PDB id:

2x2m

Name:

Transferase

Title:

Crystal structure of phosphorylated ret tyrosine kinase domain with inhibitor

Structure:

Proto-oncogene tyrosine-protein kinase receptor ret. Chain: a, b. Fragment: tyrosine kinase domain, residues 705-1013. Synonym: ret tyrosine kinase receptor, c-ret. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.50Å R-factor: 0.203 R-free: 0.242

Authors:

P.P.Knowles,J.Murray-Rust,S.Kjaer,N.Q.Mcdonald

Key ref:

L.Mologni et al. (2010). Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors. Bioorg Med Chem Lett, 18, 1482-1496. PubMed id: 20117004

Date:

13-Jan-10 Release date: 09-Feb-10

Protein chains

P07949  (RET_HUMAN) -  Proto-oncogene tyrosine-protein kinase receptor Ret from Homo sapiens

Seq: 1114 a.a.

Struc: 287 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

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

Bioorg Med Chem Lett 18:1482-1496 (2010)

PubMed id: 20117004

Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.

L.Mologni, R.Rostagno, S.Brussolo, P.P.Knowles, S.Kjaer, J.Murray-Rust, E.Rosso, A.Zambon, L.Scapozza, N.Q.McDonald, V.Lucchini, C.Gambacorti-Passerini.

ABSTRACT

The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers.