3DQW: C-Src Kinase Domain Thr338ile Mutant In Complex With Atpgs

Citation:
Abstract
Protein kinases targeted by small-molecule inhibitors develop resistance through mutation of the 'gatekeeper' threonine residue of the active site. Here we show that the gatekeeper mutation in the cellular forms of c-ABL, c-SRC, platelet-derived growth factor receptor-alpha and -beta, and epidermal growth factor receptor activates the kinase and promotes malignant transformation of BaF3 cells. Structural analysis reveals that a network of hydrophobic interactions-the hydrophobic spine-characteristic of the active kinase conformation is stabilized by the gatekeeper substitution. Substitution of glycine for the residues constituting the spine disrupts the hydrophobic connectivity and inactivates the kinase. Furthermore, a small-molecule inhibitor that maximizes complementarity with the dismantled spine (compound 14) inhibits the gatekeeper mutation of BCR-ABL-T315I. These results demonstrate that mutation of the gatekeeper threonine is a common mechanism of activation for tyrosine kinases and provide structural insights to guide the development of next-generation inhibitors.
PDB ID: 3DQWDownload
MMDB ID: 66944
PDB Deposition Date: 2008/7/9
Updated in MMDB: 2008/10
Experimental Method:
x-ray diffraction
Resolution: 2.02  Å
Source Organism:
Similar Structures:
Biological Unit for 3DQW: monomeric; determined by software (PISA)
Molecular Components in 3DQW
Label Count Molecule
Protein (1 molecule)
1
Proto-oncogene Tyrosine-protein Kinase SRC(Gene symbol: SRC)
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

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