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The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core.促凋亡蛋白 BAX 的构象稳定性由其蛋白核心的离散残基决定。
Nat Commun. 2021 Aug 13;12(1):4932. doi: 10.1038/s41467-021-25200-7.
2
BAX mitochondrial integration is regulated allosterically by its α1-α2 loop.BAX 线粒体整合受其 α1-α2 环的变构调节。
Cell Death Differ. 2021 Dec;28(12):3270-3281. doi: 10.1038/s41418-021-00815-x. Epub 2021 Jun 16.
3
An amphipathic Bax core dimer forms part of the apoptotic pore wall in the mitochondrial␣membrane.两亲性 Bax 核心二聚体构成线粒体外膜凋亡孔壁的一部分。
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4
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Further lead optimization on Bax activators: Design, synthesis and pharmacological evaluation of 2-fluoro-fluorene derivatives for the treatment of breast cancer.进一步优化 Bax 激活剂：用于治疗乳腺癌的 2-氟芴衍生物的设计、合成与药理学评价。
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6
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Pore formation in regulated cell death.调控细胞死亡中的孔形成。
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BAX的生理与药理调节

Physiological and pharmacological modulation of BAX.

作者信息

Spitz Adam Z, Gavathiotis Evripidis

机构信息

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA; Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA.

出版信息

Trends Pharmacol Sci. 2022 Mar;43(3):206-220. doi: 10.1016/j.tips.2021.11.001. Epub 2021 Nov 27.

DOI:10.1016/j.tips.2021.11.001
PMID:34848097
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8840970/
Abstract

Bcl-2-associated X protein (BAX) is a critical executioner of mitochondrial regulated cell death through its lethal activity of permeabilizing the mitochondrial outer membrane (MOM). While the physiological function of BAX ensures tissue homeostasis, dysregulation of BAX leads to aberrant cell death. Despite BAX being a promising therapeutic target for human diseases, historically the development of drugs has focused on antiapoptotic BCL-2 proteins, due to challenges in elucidating the mechanism of BAX activation and identifying druggable surfaces of BAX. Here, we discuss recent studies that have provided structure-function insights and identified regulatory surfaces that control BAX activation. Moreover, we emphasize the development of small molecule orthosteric, allosteric, and oligomerization modulators that provide novel opportunities for biological investigation and progress towards drugging BAX.

摘要

Bcl-2相关X蛋白（BAX）是线粒体调控细胞死亡的关键执行者，它具有使线粒体外膜（MOM）通透的致死活性。虽然BAX的生理功能可确保组织稳态，但BAX的失调会导致异常细胞死亡。尽管BAX是人类疾病很有前景的治疗靶点，但由于在阐明BAX激活机制和确定BAX的可成药表面方面存在挑战，历史上药物研发一直聚焦于抗凋亡BCL-2蛋白。在此，我们讨论了近期的研究，这些研究提供了结构-功能方面的见解，并确定了控制BAX激活的调控表面。此外，我们强调了小分子正构、别构和寡聚化调节剂的开发，这些调节剂为生物学研究以及BAX药物研发带来了新机遇。