Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations

Richard W. Birkinshaw; Jia-nan Gong; Cindy S. Luo; Daisy Lio; Christine A. White; Mary Ann Anderson; Piers Blombery; Guillaume Lessene; Ian J. Majewski; Rachel Thijssen; Andrew W. Roberts; David C. S. Huang; Peter M. Colman; Peter E. Czabotar

doi:10.1038/s41467-019-10363-1

Nature Communications (Jun 2019)

Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations

Richard W. Birkinshaw,
Jia-nan Gong,
Cindy S. Luo,
Daisy Lio,
Christine A. White,
Mary Ann Anderson,
Piers Blombery,
Guillaume Lessene,
Ian J. Majewski,
Rachel Thijssen,
Andrew W. Roberts,
David C. S. Huang,
Peter M. Colman,
Peter E. Czabotar

Affiliations

Richard W. Birkinshaw: Walter and Eliza Hall Institute of Medical Research
Jia-nan Gong: Walter and Eliza Hall Institute of Medical Research
Cindy S. Luo: Walter and Eliza Hall Institute of Medical Research
Daisy Lio: Walter and Eliza Hall Institute of Medical Research
Christine A. White: Walter and Eliza Hall Institute of Medical Research
Mary Ann Anderson: Walter and Eliza Hall Institute of Medical Research
Piers Blombery: Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital
Guillaume Lessene: Walter and Eliza Hall Institute of Medical Research
Ian J. Majewski: Walter and Eliza Hall Institute of Medical Research
Rachel Thijssen: Walter and Eliza Hall Institute of Medical Research
Andrew W. Roberts: Walter and Eliza Hall Institute of Medical Research
David C. S. Huang: Walter and Eliza Hall Institute of Medical Research
Peter M. Colman: Walter and Eliza Hall Institute of Medical Research
Peter E. Czabotar: Walter and Eliza Hall Institute of Medical Research

DOI: https://doi.org/10.1038/s41467-019-10363-1
Journal volume & issue: Vol. 10, no. 1
pp. 1 – 10

Abstract

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The BCL-2 mutation G101V reduces venetoclax affinity and confers drug resistance in patients with chronic lymphocytic leukaemia. Here, the authors present crystal structures and biochemical analyses of venetoclax bound to BCL-2 and the G101V mutant, revealing the structural basis for venetoclax resistance.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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