Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
- Author(s)
- Birkinshaw, RW; Gong, JN; Luo, CS; Lio, D; White, CA; Anderson, MA; Blombery, P; Lessene, G; Majewski, IJ; Thijssen, R; Roberts, AW; Huang, DCS; Colman, PM; Czabotar, PE;
- Details
- Publication Year 2019-06-03,Volume 10,Issue #1,Page 2385
- Journal Title
- Nature Communications
- Publication Type
- Journal Article
- Abstract
- Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.
- Publisher
- Springer Nature
- Research Division(s)
- Structural Biology; Blood Cells And Blood Cancer; Chemical Biology
- PubMed ID
- 31160589
- Publisher's Version
- https://doi.org/10.1038/s41467-019-10363-1
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-019-10363-1- NHMRC Grants
- NHMRC/1059331, NHMRC/1079706, NHMRC/1113577, NHMRC/1116934, NHMRC/1079700,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-06-14 09:36:56
Last Modified: 2019-06-14 11:01:00