Journal article
Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
RW Birkinshaw, JN Gong, CS Luo, D Lio, CA White, MA Anderson, P Blombery, G Lessene, IJ Majewski, R Thijssen, AW Roberts, DCS Huang, PM Colman, PE Czabotar
Nature Communications | Published : 2019
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 th..
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Funding Acknowledgements
Research in the authors' laboratory is supported by NHMRC project grants (1059331 and 1079706), program grants (11131233 DCSH, PMC; 1113577 AWR) and fellowships (1156024 DCSH, 1079560 AWR, 1116934 PMC, 1079700 PEC), the Leukemia and Lymphoma Society (SCOR 7015-18 and Fellowship 5467-18 to RT), the Victorian Cancer Agency (Fellowship to IJM), project support from The Cancer Council of Victoria (Project 1124178 to IJM), the Victorian State Government Operational Infrastructure Support, and the Australian Government NHMRC IRIISS. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. The authors would like to thank Yan-Hong Tan for technical assistance, Dr W. Douglas Fairlie and Dr Erina Lee for providing BCL-2 plasmid DNA and the Collaborative Crystallisation Centre (C3, CSIRO) for crystallisation screening. We would also like to thank Wayne Fairbrother for discussions related to the manuscript. Finally the authors would like to thank the following cats and their owners for donating their naturally shedded whiskers for crystallisation seeding experiments: Tilly, Boris, Patsy and Snoop Catty Cat.