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Picky ABCG5/G8 and promiscuous ABCG2 ‐ a tale of fatty diets and drug toxicity
Structural data on ABCG5/G8 and ABCG2 reveal a unique molecular architecture for subfamily G ATP‐binding cassette (ABCG) transporters and disclose putative substrate‐binding sites. ABCG5/G8 and ABCG2 appear to use several unique structural motifs to execute transport, including the triple helical bu...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756502/ https://www.ncbi.nlm.nih.gov/pubmed/32978801 http://dx.doi.org/10.1002/1873-3468.13938 |
Sumario: | Structural data on ABCG5/G8 and ABCG2 reveal a unique molecular architecture for subfamily G ATP‐binding cassette (ABCG) transporters and disclose putative substrate‐binding sites. ABCG5/G8 and ABCG2 appear to use several unique structural motifs to execute transport, including the triple helical bundles, the membrane‐embedded polar relay, the re‐entry helices, and a hydrophobic valve. Interestingly, ABCG2 shows extreme substrate promiscuity, whereas ABCG5/G8 transports only sterol molecules. ABCG2 structures suggest a large internal cavity, serving as a binding region for substrates and inhibitors, while mutational and pharmacological analyses support the notion of multiple binding sites. By contrast, ABCG5/G8 shows a collapsed cavity of insufficient size to hold substrates. Indeed, mutational analyses indicate a sterol‐binding site at the hydrophobic interface between the transporter and the lipid bilayer. In this review, we highlight key differences and similarities between ABCG2 and ABCG5/G8 structures. We further discuss the relevance of distinct and shared structural features in the context of their physiological functions. Finally, we elaborate on how ABCG2 and ABCG5/G8 could pave the way for studies on other ABCG transporters. |
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