2X2M

Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor

Summary for 2X2M

• Entry DOI: 10.2210/pdb2x2m/pdb
• Related: 2IVS 2IVT 2IVU 2IVV 2X2K 2X2L
• Descriptor: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET, FORMIC ACID, (3Z)-3-[(3,5-DIMETHYL-1H-PYRROL-2-YL)METHYLIDENE]-1,3-DIHYDRO-2H-INDOL-2-ONE, ... (4 entities in total)
• Functional Keywords: hirschsprung disease, gdnf receptor, transmembrane, proto-oncogene, phosphoprotein, disease mutation, phosphotransferase, ret, kinase, membrane, transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 72283.12

Authors

Knowles, P.P.,Murray-Rust, J.,Kjaer, S.,McDonald, N.Q. (deposition date: 2010-01-13, release date: 2010-02-09, Last modification date: 2023-12-20)

Primary citation

Mologni, L.,Rostagno, R.,Brussolo, S.,Knowles, P.P.,Kjaer, S.,Murray-Rust, J.,Rosso, E.,Zambon, A.,Scapozza, L.,McDonald, N.Q.,Lucchini, V.,Gambacorti-Passerini, C.
Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
Bioorg. Med. Chem., 18:1482-1496, 2010

PubMed 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.

PubMed: 20117004
DOI: 10.1016/j.bmc.2010.01.011

Experimental method

X-RAY DIFFRACTION (2.5 Å)