9BIS

Cryo-EM structure of the mammalian peptide transporter PepT2 bound to amoxicillin

Summary for 9BIS

• Entry DOI: 10.2210/pdb9bis/pdb
• EMDB information: 44600
• Descriptor: Solute carrier family 15 member 2, nanobody, 2-{1-[2-AMINO-2-(4-HYDROXY-PHENYL)-ACETYLAMINO]-2-OXO-ETHYL}-5,5-DIMETHYL-THIAZOLIDINE-4-CARBOXYLIC ACID (3 entities in total)
• Functional Keywords: protein-coupled peptide transporter, peptide transport, antibiotics, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 2
• Total formula weight: 97339.37

Authors

Parker, J.L.,Deme, J.C.,Lea, S.M.,Newstead, S. (deposition date: 2024-04-24, release date: 2024-07-24, Last modification date: 2024-11-13)

Primary citation

Parker, J.L.,Deme, J.C.,Lichtinger, S.M.,Kuteyi, G.,Biggin, P.C.,Lea, S.M.,Newstead, S.
Structural basis for antibiotic transport and inhibition in PepT2.
Nat Commun, 15:8755-8755, 2024

PubMed Abstract: 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.

PubMed: 39384780
DOI: 10.1038/s41467-024-53096-6

Experimental method

ELECTRON MICROSCOPY (3.2 Å)