3DQW

c-Src kinase domain Thr338Ile mutant in complex with ATPgS

Summary for 3DQW

• Entry DOI: 10.2210/pdb3dqw/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: src, kinase, active, gatekeeper, atp-binding, lipoprotein, myristate, nucleotide-binding, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase
• Biological source: Gallus gallus (chicken)
• Cellular location: Cell membrane (By similarity): P00523
• Total number of polymer chains: 4
• Total formula weight: 133464.91

Authors

Azam, M.,Seeliger, M.A.,Gray, N.,Kuriyan, J.,Daley, G.Q. (deposition date: 2008-07-09, release date: 2008-09-23, Last modification date: 2023-11-15)

Primary citation

Azam, M.,Seeliger, M.A.,Gray, N.S.,Kuriyan, J.,Daley, G.Q.
Activation of tyrosine kinases by mutation of the gatekeeper threonine.
Nat.Struct.Mol.Biol., 15:1109-1118, 2008

PubMed 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.

PubMed: 18794843
DOI: 10.1038/nsmb.1486

Experimental method

X-RAY DIFFRACTION (2.017 Å)