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

被引：177

作者：

Birkinshaw, Richard W. ^{[1
,2
]}

Gong, Jia-nan ^{[1
,2
]}

Luo, Cindy S. ^{[1
,2
]}

Lio, Daisy ^{[1
,2
]}

White, Christine A. ^{[1
,2
]}

Anderson, Mary Ann ^{[1
,2
,3
,4
]}

Blombery, Piers ^{[3
,4
,5
,6
]}

Lessene, Guillaume ^{[1
,2
,7
]}

Majewski, Ian J. ^{[1
,2
]}

Thijssen, Rachel ^{[1
,2
]}

Roberts, Andrew W. ^{[1
,2
,3
,4
,8
,9
]}

Huang, David C. S. ^{[1
,2
]}

Colman, Peter M. ^{[1
,2
]}

Czabotar, Peter E. ^{[1
,2
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, 1G Royal Parade, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3052, Australia

[3] Peter MacCallum Canc Ctr, Clin Haematol, Melbourne, Vic 3000, Australia

[4] Royal Melbourne Hosp, Melbourne, Vic 3000, Australia

[5] Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic 3000, Australia

[6] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3000, Australia

[7] Univ Melbourne, Dept Pharmacol & Therapeut, Melbourne, Vic 3010, Australia

[8] Univ Melbourne, Ctr Canc Res, Melbourne, Vic 3000, Australia

[9] Victorian Comprehens Canc Ctr, Melbourne, Vic 3000, Australia

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

FAMILY PROTEINS; CRYSTAL-STRUCTURE; INHIBITOR; POTENT; ANTAGONISTS; APOPTOSIS; ABT-199; MCL-1;

D O I：

10.1038/s41467-019-10363-1

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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