Stauffer Mirko, Jeckelmann Jean-Marc, Ilgü Hüseyin, Ucurum Zöhre, Boggavarapu Rajendra, Fotiadis Dimitrios
Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA.
Commun Chem. 2022 Feb 24;5(1):23. doi: 10.1038/s42004-022-00636-0.
Inhibitors for membrane transporters have been shown to be indispensable as drugs and tool compounds. The proton-dependent oligopeptide transporters PEPT1 and PEPT2 from the SLC15 family play important roles in human and mammalian physiology. With Lys[Z(NO)]-Val (LZNV), a modified Lys-Val dipeptide, a potent transport inhibitor for PEPT1 and PEPT2 is available. Here we present the crystal structure of the peptide transporter YePEPT in complex with LZNV. The structure revealed the molecular interactions for inhibitor binding and a previously undescribed mostly hydrophobic pocket, the PZ pocket, involved in interaction with LZNV. Comparison with a here determined ligand-free structure of the transporter unveiled that the initially absent PZ pocket emerges through conformational changes upon inhibitor binding. The provided biochemical and structural information constitutes an important framework for the mechanistic understanding of inhibitor binding and action in proton-dependent oligopeptide transporters.
膜转运蛋白抑制剂已被证明作为药物和工具化合物是不可或缺的。溶质载体家族15（SLC15）中的质子依赖性寡肽转运蛋白PEPT1和PEPT2在人类和哺乳动物生理学中发挥着重要作用。利用Lys[Z(NO)]-Val（LZNV），一种修饰的Lys-Val二肽，可获得一种有效的PEPT1和PEPT2转运抑制剂。在此，我们展示了肽转运蛋白YePEPT与LZNV复合物的晶体结构。该结构揭示了抑制剂结合的分子相互作用以及一个先前未描述的主要为疏水的口袋，即PZ口袋，其参与与LZNV的相互作用。与这里测定的转运蛋白的无配体结构比较表明，最初不存在的PZ口袋通过抑制剂结合后的构象变化而出现。所提供的生化和结构信息构成了一个重要框架，用于从机制上理解质子依赖性寡肽转运蛋白中抑制剂的结合和作用。
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