Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
Structures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
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DOI：
10.1038/s41467-019-10363-1
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发表时间：
2019-06-03
影响因子：
16.6
通讯作者：
Czabotar, Peter E.
中科院分区：
文献类型：
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作者：
Birkinshaw, Richard W.;Gong, Jia-nan;Czabotar, Peter E.
维奈托克是一种一流的癌症治疗药物，与细胞凋亡机制相互作用，促进细胞凋亡。用这种BCL-2拮抗剂治疗慢性淋巴细胞白血病患者，发现在一些治疗失败的患者中出现药物选择性BCL-2突变（G101 V）。为了了解这种获得性耐药性的分子基础，我们描述了与BCL-2和G101 V突变体结合的维奈托克的晶体结构。维奈托克在BCL-2上的结合位点的姿势与已发表的维奈托克类似物的复合物结构相比，显示出小但意想不到的差异。G101 V突变体复合物结构和突变体结合试验表明，抗性是通过V101对相邻残基E152的敲入效应获得的，其中维奈托克结合通过E152 A突变恢复。这为考虑可能有效对抗这种突变的venetoclax类似物提供了一个框架。
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.