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PDBsum entry 2x2m

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2x2m
Jmol
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:   0.241
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, 18, 1482-1496. PubMed id: 20117004 DOI: 10.1016/j.bmc.2010.01.011
Date:
13-Jan-10     Release date:   09-Feb-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P07949  (RET_HUMAN) -  Proto-oncogene tyrosine-protein kinase receptor Ret
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1114 a.a.
287 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* 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.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+
[protein]-L-tyrosine
Bound ligand (Het Group name = X2M)
matches with 52.00% similarity
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.bmc.2010.01.011 Bioorg Med Chem 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.