Cell Discovery：于杰团队揭示肌酸转运蛋白CRT的底物识别和抑制机制

Core Viewpoint - Creatine plays a crucial role in energy metabolism within muscle and brain tissues, acting as an energy buffer, particularly during high-intensity neuronal activity. The genetic mutation of the creatine transporter protein (CRT) leads to X-linked creatine transporter deficiency (CTD), which currently lacks effective treatment options. A compound in phase II clinical trials, RGX-202, inhibits CRT's function, inducing apoptosis in tumor cells and suppressing colorectal cancer growth [2][6]. Group 1 - The study published in Cell Discovery details the cryo-electron microscopy structure of human CRT in various states, elucidating the molecular mechanisms of substrate and inhibitor recognition [3][6]. - The research team utilized molecular dynamics simulations and functional experiments to explore the impact of pathogenic mutations on CRT function and cellular localization [3][6]. - The findings provide a theoretical basis and structural foundation for the future development of therapeutic drugs targeting CTD [6]. Group 2 - The study reveals that creatine binds to CRT in an outward-open conformation, undergoing a conformational change in the presence of Na+ and Cl- to an inward-closed state, ultimately releasing creatine into the cytoplasm [5][6]. - RGX-202 inhibits CRT function by directly competing for the creatine binding site, highlighting its mechanism of action [5][6]. - The research was supported by various funding sources, including the Shanghai Municipal Basic Research and the Shanghai Aging Research Key Laboratory [6].