9v8w

membrane protein S6A8 with RGX

spinqualitylabelsall models 9v8w, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9v8w is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.75Å Ligands: A1D9S, CL, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SC6A8_HUMAN X-linked creatine transporter deficiency. The disease is caused by variants affecting the gene represented in this entry. Function SC6A8_HUMAN Creatine:sodium symporter which mediates the uptake of creatine (PubMed:17465020, PubMed:22644605, PubMed:25861866, PubMed:7945388, PubMed:7953292, PubMed:9882430). Plays an important role in supplying creatine to the brain via the blood-brain barrier (By similarity).[UniProtKB:Q8VBW1] Publication Abstract from PubMed 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. Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT).,Yuan X, Yin J, Liu C, Chen X, Chen M, Wang Y, Yang Z, Wang Y, Jiang L, Zhou N, Wang X, Liu B, Ma Z, Wang K, Li H, Zhang S, Shang Y, Yang M Proc Natl Acad Sci U S A. 2025 Sep 9;122(36):e2426135122. doi: , 10.1073/pnas.2426135122. Epub 2025 Sep 2. PMID:40892912 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA