The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
Open accessAbstract
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.
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Metadata
- Authors
- Birkinshaw, R. W., Gong, J.-N., Luo, C. S., Lio, D., White, C. A., Anderson, M. A., Blombery, P., Lessene, G., Majewski, I. J., Thijssen, R., Roberts, A. W., Huang, D. C. S., Colman, P. M., & Czabotar, P. E.
- Venue
- Nature Communications
- Published
- 2019-06-03
- Volume
- 10
- Issue
- 1
- Pages
- 2385-2385
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W2945386002
- Cited by
- 254
- References
- 7
- FWCI
- 7.95
- Type
- journal article
- Language
- en
- Open access
- gold
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- Birkinshaw, R. W., Gong, J.-N., Luo, C. S., Lio, D., White, C. A., Anderson, M. A., Blombery, P., Lessene, G., Majewski, I. J., Thijssen, R., Roberts, A. W., Huang, D. C. S., Colman, P. M., & Czabotar, P. E. (2019). Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations. Nature Communications. https://doi.org/10.1038/s41467-019-10363-1
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