3EL8
Crystal structure of c-Src in complex with pyrazolopyrimidine 5
Summary for 3EL8
| Entry DOI | 10.2210/pdb3el8/pdb |
| Related | 3EL7 |
| Descriptor | Proto-oncogene tyrosine-protein kinase Src, 1-{4-[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl}-3-[3-(trifluoromethyl)phenyl]urea (3 entities in total) |
| Functional Keywords | c-src, kinase, pyrazolopyrimidine 5, 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 | 65908.73 |
| Authors | Dar, A.C.,Lopez, M.S.,Shokat, K.M. (deposition date: 2008-09-20, release date: 2008-10-28, Last modification date: 2023-08-30) |
| Primary citation | Dar, A.C.,Lopez, M.S.,Shokat, K.M. Small molecule recognition of c-Src via the Imatinib-binding conformation. Chem.Biol., 15:1015-1022, 2008 Cited by PubMed Abstract: The cancer drug, Imatinib, is a selective Abl kinase inhibitor that does not inhibit the closely related kinase c-Src. This one drug and its ability to selectively inhibit Abl over c-Src has been a guiding principle in virtually all kinase drug discovery efforts in the last 15 years. A prominent hypothesis explaining the selectivity of Imatinib is that Abl has an intrinsic ability to adopt an inactive conformation (termed DFG-out), whereas c-Src appears to pay a high intrinsic energetic penalty for adopting this conformation, effectively excluding Imatinib from its ATP pocket. This explanation of the difference in binding affinity of Imatinib for Abl versus c-Src makes the striking prediction that it would not be possible to design an inhibitor that binds to the DFG-out conformation of c-Src with high affinity. We report the discovery of a series of such inhibitors. We use structure-activity relationships and X-ray crystallography to confirm our findings. These studies suggest that small molecules are capable of inducing the generally unfavorable DFG-out conformation in c-Src. Structural comparison between c-Src in complex with these inhibitors allows us to speculate on the differential selectivity of Imatinib for c-Src and Abl. PubMed: 18940662DOI: 10.1016/j.chembiol.2008.09.007 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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