Álvarez-Fernández Laura, Millán-García Alicia, Merino Gracia, Blanco-Paniagua Esther
Department of Biomedical Sciences-Physiology, Faculty of Veterinary Medicine, Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), University of León, Campus de Vegazana s/n, 24071 León, Spain.
Int J Mol Sci. 2025 Jun 25;26(13):6119. doi: 10.3390/ijms26136119.
ABCG2 is a crucial ATP-binding cassette (ABC) transporter involved in multidrug resistance and essential physiological and pharmacological processes. In recent years, multiple ABCG2 structures have been resolved using cryo-electron microscopy (cryo-EM), providing significant insights into its conformational states during its transport cycle. However, even more than 25 years after its description, a high-resolution X-ray crystallographic structure is still unavailable, limiting the understanding of its dynamic transitions, as well as leaving aspects of the transport cycle unresolved and open to discussion. Given the complexity of ABCG2, a multidisciplinary approach is essential in order to fully elucidate its mechanism. This review compiles recent advances in ABCG2 structural biology, highlights unresolved controversies, and explores future directions to bridge the gap between structure and function. Moving forward, integrating multiple structural and functional approaches will be key to uncovering the intricate workings of this enigmatic transporter. In particular, detailed structural insights will be crucial to identifying new ABCG2 substrates and designing selective inhibitors, with important implications for therapeutic development.
ABCG2是一种关键的ATP结合盒（ABC）转运蛋白，参与多药耐药以及重要的生理和药理过程。近年来，通过冷冻电子显微镜（cryo-EM）解析了多个ABCG2结构，为其转运循环过程中的构象状态提供了重要见解。然而，即便在其被描述超过25年后，高分辨率的X射线晶体学结构仍然无法获得，这限制了对其动态转变的理解，同时也使得转运循环的某些方面尚未得到解决且有待讨论。鉴于ABCG2的复杂性，采用多学科方法对于全面阐明其机制至关重要。本综述汇集了ABCG2结构生物学的最新进展，突出了尚未解决的争议，并探索了弥合结构与功能之间差距的未来方向。展望未来，整合多种结构和功能方法将是揭示这种神秘转运蛋白复杂运作机制的关键。特别是，详细的结构见解对于识别新的ABCG2底物和设计选择性抑制剂至关重要，这对治疗学发展具有重要意义。
