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PDBsum entry 2qi8
Go to PDB code: 
protein ligands Protein-protein interface(s) links
Signaling protein, transferase PDB id
2qi8

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
255 a.a. *
Ligands
GOL
Waters ×172
* Residue conservation analysis
PDB id:
2qi8
Name: Signaling protein, transferase
Title: Crystal structure of drug resistant src kinase domain
Structure: Proto-oncogene tyrosine-protein kinase src. Chain: a, b. Synonym: p60-src. C-src. Pp60c-src. Engineered: yes. Mutation: yes
Source: Gallus gallus. Chicken. Organism_taxid: 9031. Gene: src. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.32Å     R-factor:   0.209     R-free:   0.280
Authors: A.Michalczyk,H.B.Rode,C.Gruetter,D.Rauh
Key ref: A.Michalczyk et al. (2008). Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR. Bioorg Med Chem Lett, 16, 3482-3488. PubMed id: 18316192 DOI: 10.1016/j.bmc.2008.02.053
Date:
03-Jul-07     Release date:   18-Mar-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00523  (SRC_CHICK) -  Proto-oncogene tyrosine-protein kinase Src from Gallus gallus
Seq:
Struc: 		 
Seq:
Struc: 		533 a.a.
255 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.2  - non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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.bmc.2008.02.053 Bioorg Med Chem Lett 16:3482-3488 (2008)
PubMed id: 18316192  
 
 
Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR.
A.Michalczyk, S.Klüter, H.B.Rode, J.R.Simard, C.Grütter, M.Rabiller, D.Rauh.
 
  ABSTRACT  
 
Resistance to kinase-targeted cancer drugs has recently been linked to a single point mutation in the ATP binding site of the kinase. In EGFR, the crucial Thr790 gatekeeper residue is mutated to a Met and prevents reversible ATP competitive inhibitors from binding. Irreversible 4-(phenylamino)quinazolines have been shown to overcome this drug resistance and are currently in clinical trials. In order to obtain a detailed structural understanding of how irreversible inhibitors overcome drug resistance, we used Src kinase as a model system for drug resistant EGFR-T790M. We report the first crystal structure of a drug resistant kinase in complex with an irreversible inhibitor. This 4-(phenylamino)quinazoline inhibits wild type and drug resistant EGFR in vitro at low nM concentrations. The co-crystal structure of drug resistant cSrc-T338M kinase domain provides the structural basis of this activity.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20336692 M.Rabiller, M.Getlik, S.Klüter, A.Richters, S.Tückmantel, J.R.Simard, and D.Rauh (2010).
Proteus in the world of proteins: conformational changes in protein kinases.
  Arch Pharm (Weinheim), 343, 193-206.  
19455431 R.Rajasekaran, and R.Sethumadhavan (2010).
In silico identification of significant detrimental missense mutations of EGFR and their effect with 4-anilinoquinazoline-based drugs.
  Appl Biochem Biotechnol, 160, 1723-1733.  
21080395 S.Klüter, J.R.Simard, H.B.Rode, C.Grütter, V.Pawar, H.C.Raaijmakers, T.A.Barf, M.Rabiller, W.A.van Otterlo, and D.Rauh (2010).
Characterization of irreversible kinase inhibitors by directly detecting covalent bond formation: a tool for dissecting kinase drug resistance.
  Chembiochem, 11, 2557-2566.
PDB code: 3lok
19822424 J.Li, T.S.Kaoud, C.Laroche, K.N.Dalby, and S.M.Kerwin (2009).
Synthesis and biological evaluation of p38alpha kinase-targeting dialkynylimidazoles.
  Bioorg Med Chem Lett, 19, 6293-6297.  
19396179 J.R.Simard, S.Klüter, C.Grütter, M.Getlik, M.Rabiller, H.B.Rode, and D.Rauh (2009).
A new screening assay for allosteric inhibitors of cSrc.
  Nat Chem Biol, 5, 394-396.
PDB codes: 3f3t 3f3u
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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