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Allosteric inhibition of antiapoptotic MCL-1.

Abstract：

:MCL-1 is an antiapoptotic BCL-2 family protein that has emerged as a major pathogenic factor in human cancer. Like BCL-2, MCL-1 bears a surface groove whose function is to sequester the BH3 killer domains of proapoptotic BCL-2 family members, a mechanism harnessed by cancer cells to establish formidable apoptotic blockades. Although drugging the BH3-binding groove has been achieved for BCL-2, translating this approach to MCL-1 has been challenging. Here, we report an alternative mechanism for MCL-1 inhibition by small-molecule covalent modification of C286 at a new interaction site distant from the BH3-binding groove. Our structure-function analyses revealed that the BH3 binding capacity of MCL-1 and its suppression of BAX are impaired by molecular engagement, a phenomenon recapitulated by C286W mutagenic mimicry in vitro and in mouse cells. Thus, we characterize an allosteric mechanism for disrupting the antiapoptotic BH3 binding activity of MCL-1, informing a new strategy for disarming MCL-1 in cancer.

journal_name

Nat Struct Mol Biol

journal_title

Nature structural & molecular biology

authors

Lee S,Wales TE,Escudero S,Cohen DT,Luccarelli J,Gallagher CG,Cohen NA,Huhn AJ,Bird GH,Engen JR,Walensky LD

doi

10.1038/nsmb.3223

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

600-7

issue

6

eissn

1545-9993

issn

1545-9985

pii

nsmb.3223

journal_volume

23

pub_type

杂志文章

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