Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT)

Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na<sup>+</sup>/Cl<sup>-</sup>-dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-09-02
DOI
https://doi.org/10.1073/pnas.2426135122
Citations
2
Primary Topic
Muscle metabolism and nutrition
Type
article
Field-Weighted Citation Impact
2.30

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article

Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT)

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2 citations
Proceedings of the National Academy of Sciences
Muscle metabolism and nutrition
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article

Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT)

Meiying Chen, Li Jiang, Sensen Zhang, Botong Liu, Yue Wang, Yixue Wang, Maojun Yang, Niyun Zhou, Hongen Li, Yongfeng Shang, Kaiyan Wang, Chang Liu, Xiaojuan Wang, Jian Yin, Xinyi Yuan, Xudong Chen, Zi Yang, Z. Ma
article en
2 citations

Abstract

Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na<sup>+</sup>/Cl<sup>-</sup>-dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.

Proceedings of the National Academy of SciencesVol. 122(36)
Hangzhou Normal University (CN), Peking University (CN), King Center (US), Chinese General Hospital College of Nursing and Liberal Arts (PH), People's Liberation Army No. 150 Hospital (CN), Ministry of Education (KR), Beijing Children’s Hospital (CN), Center for Life Sciences (CN), Chinese People’s Liberation Army 263 hospital (CN), Beijing Academy of Science and Technology (CN), China Agricultural University (CN), Tsinghua University (CN), Air Force Medical University (CN)
National Natural Science Foundation of China, King Abdullah University of Science and Technology, Tsinghua University, National Key Research and Development Program of China, Natural Science Foundation of Zhejiang Province
Openalex Percentile: Top 12%
Muscle metabolism and nutrition
2.30
DOIOpen Access PDFOpenAlex
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