2. Academic Validation
  3. Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT)

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

  • Proc Natl Acad Sci U S A. 2025 Sep 9;122(36):e2426135122. doi: 10.1073/pnas.2426135122.
Xinyi Yuan # 1 2 3,  Jian Yin # 4,  Chang Liu # 5,  Xudong Chen # 4,  Meiying Chen 4,  Yixue Wang 4,  Zi Yang 6,  Yue Wang 1,  Li Jiang 1,  Niyun Zhou 4,  Xiaojuan Wang 7,  Botong Liu 4,  Zhaoqi Ma 8,  Kaiyan Wang 9,  Hongen Li 10,  Sensen Zhang 4 5,  Yongfeng Shang 1 3,  Maojun Yang 4 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China.
  • 2 College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 4 Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 5 Beijing Life Science Academy, Beijing 102209, China.
  • 6 Technology Center for Protein Research, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 7 Department of Endocrinology, Genetics and Metabolism, National Center for Children's Health, Beijing Children's Hospital Capital Medical University, Beijing 100045, China.
  • 8 College of Biological Science, China Agricultural University, Beijing 100083, China.
  • 9 National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shanxi 710032, China.
  • 10 Department of Ophthalmology, The Chinese People's Liberation Army General Hospital & The Chinese People's Liberation Army Medical School, Beijing 100039, China.
  • # Contributed equally.
PMID: 40892912 DOI: 10.1073/pnas.2426135122
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+/Cl--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.

Keywords

competitive inhibition; human creatine transporter; substrate uptake.

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