Tumor-acquired somatic mutation affects conformation to abolish ABCG2-mediated drug resistance

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-02-06 DOI:10.1016/j.drup.2024.101066
Tomoka Gose , Ali Rasouli , Sepehr Dehghani-Ghahnaviyeh , Po-Chao Wen , Yao Wang , John Lynch , Yu Fukuda , Talha Shafi , Robert C. Ford , Emad Tajkhorshid , John D. Schuetz
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Abstract

ABCG2 is an important ATP-binding cassette transporter impacting the absorption and distribution of over 200 chemical toxins and drugs. ABCG2 also reduces the cellular accumulation of diverse chemotherapeutic agents. Acquired somatic mutations in the phylogenetically conserved amino acids of ABCG2 might provide unique insights into its molecular mechanisms of transport. Here, we identify a tumor-derived somatic mutation (Q393K) that occurs in a highly conserved amino acid across mammalian species. This ABCG2 mutant seems incapable of providing ABCG2-mediated drug resistance. This was perplexing because it is localized properly and retained interaction with substrates and nucleotides. Using a conformationally sensitive antibody, we show that this mutant appears “locked” in a non-functional conformation. Structural modeling and molecular dynamics simulations based on ABCG2 cryo-EM structures suggested that the Q393K interacts with the E446 to create a strong salt bridge. The salt bridge is proposed to stabilize the inward-facing conformation, resulting in an impaired transporter that lacks the flexibility to readily change conformation, thereby disrupting the necessary communication between substrate binding and transport.

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肿瘤获得性体细胞突变会影响构象,从而消除 ABCG2 介导的耐药性。
ABCG2 是一种重要的 ATP 结合盒转运体,影响着 200 多种化学毒素和药物的吸收和分布。ABCG2 还能减少多种化疗药物在细胞内的蓄积。ABCG2系统保守氨基酸的获得性体细胞突变可能会对其分子转运机制提供独特的见解。在这里,我们发现了一种来自肿瘤的体细胞突变(Q393K),这种突变发生在哺乳动物物种中高度保守的氨基酸上。这种ABCG2突变体似乎无法产生ABCG2介导的耐药性。这令人费解,因为它定位正确,并能保持与底物和核苷酸的相互作用。利用构象敏感抗体,我们发现该突变体似乎被 "锁定 "在一个无功能的构象中。基于 ABCG2 低温电子显微镜结构的结构建模和分子动力学模拟表明,Q393K 与 E446 相互作用,形成了一个强大的盐桥。盐桥被认为能稳定内向构象,导致转运体功能受损,缺乏随时改变构象的灵活性,从而破坏了底物结合与转运之间的必要沟通。
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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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