3G6H

Src Thr338Ile inhibited in the DFG-Asp-Out conformation

Summary for 3G6H

• Entry DOI: 10.2210/pdb3g6h/pdb
• Related: 3G6G
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, N-{4-methyl-3-[(3-{4-[(3,4,5-trimethoxyphenyl)amino]-1,3,5-triazin-2-yl}pyridin-2-yl)amino]phenyl}-3-(trifluoromethyl)benzamide (3 entities in total)
• Functional Keywords: cancer, imatinib resistance, dsa compounds, kinase, dfg-asp-out, alternative splicing, 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: 2
• Total formula weight: 66109.00

Authors

Seeliger, M.A.,Ranjitkar, P.,Kasap, C.,Shan, Y.,Shaw, D.E.,Shah, N.P.,Kuriyan, J.,Maly, D.J. (deposition date: 2009-02-06, release date: 2009-03-24, Last modification date: 2023-09-06)

Primary citation

Seeliger, M.A.,Ranjitkar, P.,Kasap, C.,Shan, Y.,Shaw, D.E.,Shah, N.P.,Kuriyan, J.,Maly, D.J.
Equally potent inhibition of c-Src and Abl by compounds that recognize inactive kinase conformations
Cancer Res., 69:2384-2392, 2009

PubMed Abstract: Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile "gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells.

PubMed: 19276351
DOI: 10.1158/0008-5472.CAN-08-3953

Experimental method

X-RAY DIFFRACTION (2.35 Å)