Department of Biochemistry, University of Oxford, Oxford, UK.
The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
Nat Commun. 2024 Oct 9;15(1):8755. doi: 10.1038/s41467-024-53096-6.
The uptake and elimination of beta-lactam antibiotics in the human body are facilitated by the proton-coupled peptide transporters PepT1 (SLC15A1) and PepT2 (SLC15A2). The mechanism by which SLC15 family transporters recognize and discriminate between different drug classes and dietary peptides remains unclear, hampering efforts to improve antibiotic pharmacokinetics through targeted drug design and delivery. Here, we present cryo-EM structures of the proton-coupled peptide transporter, PepT2 from Rattus norvegicus, in complex with the widely used beta-lactam antibiotics cefadroxil, amoxicillin and cloxacillin. Our structures, combined with pharmacophore mapping, molecular dynamics simulations and biochemical assays, establish the mechanism of beta-lactam antibiotic recognition and the important role of protonation in drug binding and transport.
β-内酰胺类抗生素在人体内的摄取和消除是由质子偶联肽转运蛋白 PepT1（SLC15A1）和 PepT2（SLC15A2）介导的。SLC15 家族转运蛋白识别和区分不同药物类别和膳食肽的机制尚不清楚，这阻碍了通过靶向药物设计和递送来改善抗生素药代动力学的努力。在这里，我们展示了来自褐家鼠的质子偶联肽转运蛋白 PepT2 与广泛使用的β-内酰胺类抗生素头孢羟氨苄、阿莫西林和氯唑西林复合物的冷冻电镜结构。我们的结构结合药效团映射、分子动力学模拟和生化分析，确定了β-内酰胺类抗生素识别的机制以及质子化在药物结合和转运中的重要作用。
