Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10363-1
Keywords
-
Categories
Funding
- NHMRC [1059331, 1079706, 11131233, 1113577, 1156024, 1079560, 1116934, 1079700]
- Leukemia and Lymphoma Society [SCOR 7015-18, 5467-18]
- Victorian Cancer Agency
- Cancer Council of Victoria [1124178]
- Victorian State Government Operational Infrastructure Support
- Australian Government NHMRC IRIISS
- National Health and Medical Research Council of Australia [1079706, 1079700, 1059331, 1156024, 1116934] Funding Source: NHMRC
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available