Modulation of ABCG2 Transporter Activity by Ko143 Derivatives.

IF 3.5 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Biology Pub Date : 2024-10-24 DOI:10.1021/acschembio.4c00353
Qin Yu, Sepehr Dehghani-Ghahnaviyeh, Ali Rasouli, Anna Sadurni, Julia Kowal, Rose Bang-Soerensen, Po-Chao Wen, Melanie Tinzl-Zechner, Rossitza N Irobalieva, Dongchun Ni, Henning Stahlberg, Karl-Heinz Altmann, Emad Tajkhorshid, Kaspar P Locher
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Abstract

ABCG2 is a multidrug transporter that protects tissues from xenobiotics, affects drug pharmacokinetics, and contributes to multidrug resistance of cancer cells. Here, we present tetracyclic fumitremorgin C analog Ko143 derivatives, evaluate their in vitro modulation of purified ABCG2, and report four high-resolution cryo-EM structures and computational analyses to elucidate their interactions with ABCG2. We found that Ko143 derivatives that are based on a ring-opened scaffold no longer inhibit ABCG2-mediated transport activity. In contrast, closed-ring, tetracyclic analogs were highly potent inhibitors. Strikingly, the least potent of these compounds, MZ82, bound deeper into the central ABCG2 cavity than the other inhibitors and it led to partial closure of the transmembrane domains and increased flexibility of the nucleotide-binding domains. Minor structural modifications can thus convert a potent inhibitor into a compound that induces conformational changes in ABCG2 similar to those observed during binding of a substrate. Molecular dynamics simulations and free energy binding calculations further supported the correlation between reduced potency and distinct binding pose of the compounds. We introduce the highly potent inhibitor AZ99 that may exhibit improved in vivo stability.

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Ko143 衍生物对 ABCG2 转运体活性的调节。
ABCG2 是一种多药转运体,它能保护组织免受异种生物的伤害,影响药物的药代动力学,并促进癌细胞的多药耐药性。在这里,我们介绍了四环伏米曲霉素 C 类似物 Ko143 衍生物,评估了它们对纯化 ABCG2 的体外调节作用,并报告了四种高分辨率冷冻电镜结构和计算分析,以阐明它们与 ABCG2 的相互作用。我们发现,基于开环支架的 Ko143 衍生物不再抑制 ABCG2 介导的转运活性。相反,闭环四环类似物则是强效抑制剂。令人吃惊的是,这些化合物中效力最弱的 MZ82 比其他抑制剂更深入 ABCG2 的中心空腔,导致跨膜结构域部分封闭,增加了核苷酸结合结构域的灵活性。因此,微小的结构改变就能将强效抑制剂转化为诱导 ABCG2 发生构象变化的化合物,这种变化与底物结合过程中观察到的变化相似。分子动力学模拟和自由能结合计算进一步证实了药效降低与化合物不同结合姿态之间的相关性。我们介绍的高效力抑制剂 AZ99 可能具有更好的体内稳定性。
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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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