6GS7

Crystal structure of peptide transporter DtpA-nanobody in glycine buffer

6GS7 の概要

• エントリーDOI: 10.2210/pdb6gs7/pdb
• 分子名称: Dipeptide and tripeptide permease A, nanobody (2 entities in total)
• 機能のキーワード: peptide transporter, membrane protein, complex with nanobody, slc15 family member
• 由来する生物種: Escherichia coli K-12; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69370.36

構造登録者

Ural-Blimke, Y.,Flayhan, A.,Quistgaard, E.M.,Loew, C. (登録日: 2018-06-13, 公開日: 2019-01-30, 最終更新日: 2024-10-23)

主引用文献

Ural-Blimke, Y.,Flayhan, A.,Strauss, J.,Rantos, V.,Bartels, K.,Nielsen, R.,Pardon, E.,Steyaert, J.,Kosinski, J.,Quistgaard, E.M.,Low, C.
Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1.
J. Am. Chem. Soc., 141:2404-2412, 2019

PubMed Abstract: Members of the solute carrier 15 family (SLC15) transport di- and tripeptides as well as peptidomimetic drugs across the cell membrane. Structures of bacterial homologues have provided valuable information on the binding and transport of their natural substrates, but many do not transport medically relevant drugs. In contrast, a homologue from Escherichia coli, DtpA (dipeptide and tripeptide permease), shows a high similarity to human PepT1 (SLC15A1) in terms of ligand selectivity and transports a similar set of drugs. Here, we present the crystal structure of DtpA in ligand-free form (at 3.30 Å resolution) and in complex with the antiviral prodrug valganciclovir (at 2.65 Å resolution) supported by biochemical data. We show that valganciclovir unexpectedly binds with the ganciclovir moiety mimicking the N-terminal residue of a canonical peptide substrate. On the basis of a homology model we argue that this binding mode also applies to the human PepT1 transporter. Our results provide new insights into the binding mode of prodrugs and will assist the rational design of drugs with improved absorption rates.

PubMed: 30644743
DOI: 10.1021/jacs.8b11343

実験手法

X-RAY DIFFRACTION (3.3 Å)