2OIQ

Crystal Structure of chicken c-Src kinase domain in complex with the cancer drug imatinib.

2OIQ の概要

• エントリーDOI: 10.2210/pdb2oiq/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: src, kinase, imatinib, inactive, transferase
• 由来する生物種: Gallus gallus (chicken)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66131.08

構造登録者

Seeliger, M.A.,Nagar, B.,Frank, F.,Cao, X.,Henderson, M.N.,Kuriyan, J. (登録日: 2007-01-11, 公開日: 2007-03-20, 最終更新日: 2023-08-30)

主引用文献

Seeliger, M.A.,Nagar, B.,Frank, F.,Cao, X.,Henderson, M.N.,Kuriyan, J.
c-Src Binds to the Cancer Drug Imatinib with an Inactive Abl/c-Kit Conformation and a Distributed Thermodynamic Penalty.
Structure, 15:299-311, 2007

PubMed Abstract: The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the PDGF receptor. Imatinib is less effective against c-Src, which is difficult to understand because residues interacting with imatinib in crystal structures of Abl and c-Kit are conserved in c-Src. The crystal structure of the c-Src kinase domain in complex with imatinib closely resembles that of Abl*imatinib and c-Kit*imatinib, and differs significantly from the inactive "Src/CDK" conformation of the Src family kinases. Attempts to increase the affinity of c-Src for imatinib by swapping residues with the corresponding residues in Abl have not been successful, suggesting that the thermodynamic penalty for adoption of the imatinib-binding conformation by c-Src is distributed over a broad region of the structure. Two mutations that are expected to destabilize the inactive Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the free-energy balance between different inactive states is a key to imatinib binding.

PubMed: 17355866
DOI: 10.1016/j.str.2007.01.015

実験手法

X-RAY DIFFRACTION (2.07 Å)