PDF(Pubmed)
Abstract：
Glucose transporters GLUT1 belong to the major facilitator superfamily and are essential to human glucose uptake. The overexpression of GLUT1 in tumor cells designates it as a pivotal target for glycoconjugate anticancer drugs. However, the interaction mechanism of glycoconjugate drugs with GLUT1 remains largely unknown. Here, we employed all-atom molecular dynamics simulations, coupled to steered and umbrella sampling techniques, to examine the thermodynamics governing the transport of glucose and two glycoconjugate drugs (i.e., 6-D-glucose-conjugated methane sulfonate and 6-D-glucose chlorambucil) by GLUT1. We characterized the specific interactions between GLUT1 and substrates at different transport stages, including substrate recognition, transport, and releasing, and identified the key residues involved in these procedures. Importantly, our results described, for the first time, the free energy profiles of GLUT1-transporting glycoconjugate drugs, and demonstrated that H160 and W388 served as important gates to regulate their transport via GLUT1. These findings provide novel atomic-scale insights for understanding the transport mechanism of GLUT1, facilitating the discovery and rational design of GLUT1-targeted anticancer drugs.
摘要：
葡萄糖转运蛋白GLUT1属于主要的促进剂超家族，对人类葡萄糖摄取至关重要。GLUT1在肿瘤细胞中的过表达表明它是糖缀合物抗癌药物的关键靶标。然而,糖缀合物药物与GLUT1的相互作用机制尚不清楚.这里,我们采用了全原子分子动力学模拟，结合操纵和伞式采样技术，检查控制葡萄糖和两种糖缀合物药物运输的热力学(即，6-D-葡萄糖缀合的甲磺酸酯和6-D-葡萄糖苯丁酸氮芥）通过GLUT1。我们表征了GLUT1和底物之间在不同运输阶段的特定相互作用，包括底物识别，运输,释放，并确定了这些程序中涉及的关键残基。重要的是,我们的结果描述了，第一次,GLUT1转运糖缀合物药物的自由能谱，并证明H160和W388是通过GLUT1调节其运输的重要门。这些发现为理解GLUT1的转运机制提供了新的原子尺度见解，促进了GLUT1靶向抗癌药物的发现和合理设计。
