3EL7

Crystal structure of c-Src in complex with pyrazolopyrimidine 3

3EL7 の概要

• エントリーDOI: 10.2210/pdb3el7/pdb
• 関連するPDBエントリー: 3EL8
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, 1-{3-[(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl]phenyl}-3-[3-(trifluoromethyl)phenyl]urea (3 entities in total)
• 機能のキーワード: kinase, c-src, pyrazolopyrimidine, atp-binding, lipoprotein, myristate, nucleotide-binding, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase
• 由来する生物種: Gallus gallus (chicken)
• 細胞内の位置: Cell membrane (By similarity): P00523
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33222.15

構造登録者

Dar, A.C.,Lopez, M.S.,Shokat, K.M. (登録日: 2008-09-20, 公開日: 2008-10-28, 最終更新日: 2023-08-30)

主引用文献

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

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: 18940662
DOI: 10.1016/j.chembiol.2008.09.007

実験手法

X-RAY DIFFRACTION (2.8 Å)