9v8x | pdb_00009v8x

membrane protein S6A8 with Crea

Structural highlights

9v8x 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 2.85Å
Ligands:	CL, CRN, 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]^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

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^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Rosenberg EH, Martínez Muñoz C, Betsalel OT, van Dooren SJ, Fernandez M, Jakobs C, deGrauw TJ, Kleefstra T, Schwartz CE, Salomons GS. Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application. Hum Mutat. 2007 Sep;28(9):890-6. PMID:17465020 doi:10.1002/humu.20532
↑ Valayannopoulos V, Bakouh N, Mazzuca M, Nonnenmacher L, Hubert L, Makaci FL, Chabli A, Salomons GS, Mellot-Draznieks C, Brulé E, de Lonlay P, Toulhoat H, Munnich A, Planelles G, de Keyzer Y. Functional and electrophysiological characterization of four non-truncating mutations responsible for creatine transporter (SLC6A8) deficiency syndrome. J Inherit Metab Dis. 2013 Jan;36(1):103-12. PMID:22644605 doi:10.1007/s10545-012-9495-9
↑ DesRoches CL, Patel J, Wang P, Minassian B, Salomons GS, Marshall CR, Mercimek-Mahmutoglu S. Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene. Gene. 2015 Jul 10;565(2):187-91. PMID:25861866 doi:10.1016/j.gene.2015.04.011
↑ Sora I, Richman J, Santoro G, Wei H, Wang Y, Vanderah T, Horvath R, Nguyen M, Waite S, Roeske WR, et al.. The cloning and expression of a human creatine transporter. Biochem Biophys Res Commun. 1994 Oct 14;204(1):419-27. PMID:7945388 doi:10.1006/bbrc.1994.2475
↑ Nash SR, Giros B, Kingsmore SF, Rochelle JM, Suter ST, Gregor P, Seldin MF, Caron MG. Cloning, pharmacological characterization, and genomic localization of the human creatine transporter. Recept Channels. 1994;2(2):165-74 PMID:7953292
↑ Dai W, Vinnakota S, Qian X, Kunze DL, Sarkar HK. Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Arch Biochem Biophys. 1999 Jan 1;361(1):75-84. PMID:9882430 doi:10.1006/abbi.1998.0959
↑ 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. 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. PMID:40892912 doi:10.1073/pnas.2426135122

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Rosenberg EH, Martínez Muñoz C, Betsalel OT, van Dooren SJ, Fernandez M, Jakobs C, deGrauw TJ, Kleefstra T, Schwartz CE, Salomons GS. Functional characterization of missense variants in the creatine transporter gene (SLC6A8): improved diagnostic application. Hum Mutat. 2007 Sep;28(9):890-6. PMID:17465020 doi:10.1002/humu.20532

[2] Valayannopoulos V, Bakouh N, Mazzuca M, Nonnenmacher L, Hubert L, Makaci FL, Chabli A, Salomons GS, Mellot-Draznieks C, Brulé E, de Lonlay P, Toulhoat H, Munnich A, Planelles G, de Keyzer Y. Functional and electrophysiological characterization of four non-truncating mutations responsible for creatine transporter (SLC6A8) deficiency syndrome. J Inherit Metab Dis. 2013 Jan;36(1):103-12. PMID:22644605 doi:10.1007/s10545-012-9495-9

[3] DesRoches CL, Patel J, Wang P, Minassian B, Salomons GS, Marshall CR, Mercimek-Mahmutoglu S. Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene. Gene. 2015 Jul 10;565(2):187-91. PMID:25861866 doi:10.1016/j.gene.2015.04.011

[4] Sora I, Richman J, Santoro G, Wei H, Wang Y, Vanderah T, Horvath R, Nguyen M, Waite S, Roeske WR, et al.. The cloning and expression of a human creatine transporter. Biochem Biophys Res Commun. 1994 Oct 14;204(1):419-27. PMID:7945388 doi:10.1006/bbrc.1994.2475

[5] Nash SR, Giros B, Kingsmore SF, Rochelle JM, Suter ST, Gregor P, Seldin MF, Caron MG. Cloning, pharmacological characterization, and genomic localization of the human creatine transporter. Recept Channels. 1994;2(2):165-74 PMID:7953292

[6] Dai W, Vinnakota S, Qian X, Kunze DL, Sarkar HK. Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes. Arch Biochem Biophys. 1999 Jan 1;361(1):75-84. PMID:9882430 doi:10.1006/abbi.1998.0959

[7] 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. 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. PMID:40892912 doi:10.1073/pnas.2426135122

[1]

[2]

[3]

[4]

[5]

[6]

[7]

9v8x | pdb_00009v8x

membrane protein S6A8 with Crea

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools