5BMM

Src in complex with DNA-templated macrocyclic inhibitor MC25b

5BMM の概要

• エントリーDOI: 10.2210/pdb5bmm/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002183
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, macrocyclic inhibitor MC25b (3 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Gallus gallus (Chicken); 詳細
• 細胞内の位置: Cell membrane : P00523
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 66934.84

構造登録者

Georghiou, G.,Guja, K.E.,Aleem, S.,Kleiner, R.E.,Liu, D.R.,Miller, W.T.,Garcia-Diaz, M.,Seeliger, M.A. (登録日: 2015-05-22, 公開日: 2016-09-21, 最終更新日: 2023-11-15)

主引用文献

Aleem, S.U.,Georghiou, G.,Kleiner, R.E.,Guja, K.E.,Craddock, B.P.,Lyczek, A.,Chan, A.I.,Garcia-Diaz, M.,Miller, W.T.,Liu, D.R.,Seeliger, M.A.
Structural and Biochemical Basis for Intracellular Kinase Inhibition by Src-specific Peptidic Macrocycles.
Cell Chem Biol, 23:1103-1112, 2016

PubMed Abstract: Protein kinases are attractive therapeutic targets because their dysregulation underlies many diseases, including cancer. The high conservation of the kinase domain and the evolution of drug resistance, however, pose major challenges to the development of specific kinase inhibitors. We recently discovered selective Src kinase inhibitors from a DNA-templated macrocycle library. Here, we reveal the structural basis for how these inhibitors retain activity against a disease-relevant, drug-resistant kinase mutant, while maintaining Src specificity. We find that these macrocycles display a degree of modularity: two of their three variable groups interact with sites on the kinase that confer selectivity, while the third group interacts with the universally conserved catalytic lysine and thereby retains the ability to inhibit the "gatekeeper" kinase mutant. We also show that these macrocycles inhibit migration of MDA-MB-231 breast tumor cells. Our findings establish intracellular kinase inhibition by peptidic macrocycles, and inform the development of potent and specific kinase inhibitors.

PubMed: 27593110
DOI: 10.1016/j.chembiol.2016.07.017

実験手法

X-RAY DIFFRACTION (2.5 Å)