6GZ9

Crystal structure of a POT family transporter in complex with prodrug valacyclovir

Summary for 6GZ9

• Entry DOI: 10.2210/pdb6gz9/pdb
• Descriptor: Peptide ABC transporter permease, 2-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methoxy]ethyl L-valinate (3 entities in total)
• Functional Keywords: peptide transporter; prodrug complex, membrane protein
• Biological source: Staphylococcus hominis
• Total number of polymer chains: 1
• Total formula weight: 54275.38

Authors

Minhas, G.S.,Newstead, S. (deposition date: 2018-07-03, release date: 2018-12-26, Last modification date: 2024-01-17)

Primary citation

Minhas, G.S.,Newstead, S.
Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters.
Proc. Natl. Acad. Sci. U.S.A., 116:804-809, 2019

PubMed Abstract: A major challenge in drug development is the optimization of intestinal absorption and cellular uptake. A successful strategy has been to develop prodrug molecules, which hijack solute carrier (SLC) transporters for active transport into the body. The proton-coupled oligopeptide transporters, PepT1 and PepT2, have been successfully targeted using this approach. Peptide transporters display a remarkable capacity to recognize a diverse library of di- and tripeptides, making them extremely promiscuous and major contributors to the pharmacokinetic profile of several important drug classes, including beta-lactam antibiotics and antiviral and antineoplastic agents. Of particular interest has been their ability to recognize amino acid and peptide-based prodrug molecules, thereby providing a rational approach to improving drug transport into the body. However, the structural basis for prodrug recognition has remained elusive. Here we present crystal structures of a prokaryotic homolog of the mammalian transporters in complex with the antiviral prodrug valacyclovir and the peptide-based photodynamic therapy agent, 5-aminolevulinic acid. The valacyclovir structure reveals that prodrug recognition is mediated through both the amino acid scaffold and the ester bond, which is commonly used to link drug molecules to the carrier's physiological ligand, whereas 5-aminolevulinic acid makes far fewer interactions compared with physiological peptides. These structures provide a unique insight into how peptide transporters interact with xenobiotic molecules and provide a template for further prodrug development.

PubMed: 30602453
DOI: 10.1073/pnas.1813715116

Experimental method

X-RAY DIFFRACTION (3.1 Å)