Structural basis of antifolate recognition and transport by PCFT.
Structural basis of antifolate recognition and transport by PCFT.
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DOI：
10.1038/s41586-021-03579-z
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发表时间：
2021-07
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
叶酸(又称维生素B9)在细胞代谢中起着至关重要的作用，因为它是合成核酸、氨基酸和万能甲基化试剂S-腺苷甲硫氨酸的起点。叶酸缺乏与许多发育、免疫和神经疾病有关。哺乳动物不能从头合成叶酸；因此，几种系统已经进化到从饮食中摄取叶酸并将其分配到体内。质子偶联叶酸转运体(PCFT)(又称SLC46A1)通过肠道刷状缘膜和脉络丛介导叶酸摄取，是肿瘤化疗中抗叶酸药物转运的重要途径。PCFT如何识别叶酸或抗叶酸剂目前尚不清楚。在这里，我们展示了无底物状态和与新一代抗叶酸药物(培美曲塞)复合的PCFT的冷冻电子显微镜结构。我们的结果为理解抗叶酸的识别提供了结构基础，并为PCFT介导的叶酸转运的pH调节机制提供了洞察力。
Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S-adenylsmethionine. Folate deficiency is associated with a number of developmental, immune and neurological disorders. Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body. The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus, and is an important route for the delivery of antifolate drugs in cancer chemotherapy. How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT.
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影响因子：
50.5
作者：
Giovannetti, E.;Zucali, P. A.;Peters, G. J.
通讯作者：
Peters, G. J.
DOI：
10.1107/s2059798317003382
发表时间：
2017-03-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Emsley P
通讯作者：
Emsley P
影响因子：
16.8
作者：
Huo, Jiangdong;Le Bas, Audrey;Naismith, James H.
通讯作者：
Naismith, James H.
影响因子：
--
作者：
Caesar J;Reboul CF;Machello C;Kiesewetter S;Tang ML;Deme JC;Johnson S;Elmlund D;Lea SM;Elmlund H
通讯作者：
Elmlund H
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD