4C5D

Crystal structure of Bcl-xL in complex with benzoylurea compound (42)

4C5D の概要

• エントリーDOI: 10.2210/pdb4c5d/pdb
• 関連するPDBエントリー: 4C52
• 分子名称: BCL-2-LIKE PROTEIN 1, (R)-3-(4-BROMOBENZYLTHIO)-2-(3-(3-((2,4-DIFLUOROPHENYL)ETHYNYL)BENZOYL)-3-PROPYLUREIDO)PROPANOIC ACID, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: apoptosis, bcl-2
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform Bcl-X(L): Mitochondrion inner membrane (By similarity): Q07817
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38263.95

構造登録者

Roy, M.J.,Brady, R.M.,Lessene, G.,Colman, P.M.,Czabotar, P.E. (登録日: 2013-09-11, 公開日: 2014-02-05, 最終更新日: 2023-12-20)

主引用文献

Brady, R.M.,Vom, A.,Roy, M.J.,Toovey, N.,Smith, B.J.,Moss, R.M.,Hazis, E.,Huang, D.C.S.,Parisot, J.P.,Yang, H.,Street, I.P.,Colman, P.M.,Czabotar, P.E.,Baell, J.B.,Lessene, G.
De-Novo Designed Library of Benzoylureas as Inhibitors of Bcl-Xl: Synthesis, Structural and Biochemical Characterization.
J.Med.Chem., 57:1323-, 2014

PubMed Abstract: The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 μM) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.

PubMed: 24456288
DOI: 10.1021/JM401948B

実験手法

X-RAY DIFFRACTION (2.3 Å)