9R1G

Cryo-EM structure of human MATE1

Summary for 9R1G

• Entry DOI: 10.2210/pdb9r1g/pdb
• Related: 9R10 9R1E 9R1F
• EMDB information: 53508
• Descriptor: Multidrug and toxin extrusion protein 1, Heavy chain of Fab, Light chain of Fab, ... (5 entities in total)
• Functional Keywords: slc47a1, apo, fab, multidrug transporter, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 112451.69

Authors

Romane, K.,Peteani, G.,Mukherjee, S.,Kowal, J.,Rossi, L.,Hou, J.,Kossiakoff, A.,Lemmin, T.,Locher, K.P. (deposition date: 2025-04-26, release date: 2025-11-05)

Primary citation

Romane, K.,Peteani, G.,Mukherjee, S.,Kowal, J.,Rossi, L.,Hou, J.,Kossiakoff, A.A.,Lemmin, T.,Locher, K.P.
Structural basis of drug recognition by human MATE1 transporter.
Nat Commun, 16:9444-9444, 2025

PubMed Abstract: Human MATE1 (multidrug and toxin extrusion protein 1) is highly expressed in the kidney and liver, where it mediates the final step in the excretion of a broad range of cationic drugs, including the antidiabetic drug metformin, into the urine and bile. This transport process is essential for drug clearance and also affects therapeutic efficacy. To understand the molecular basis of drug recognition by hMATE1, we determined cryo-electron microscopy structures of the transporter in complex with the substrates 1-methyl-4-phenylpyridinium (MPP) and metformin and with the inhibitor cimetidine. The structures reveal a shared binding site located in a negatively charged pocket in the C-lobe of the protein. We functionally validated key interactions using radioactivity-based cellular uptake assays using hMATE1 mutants. Molecular dynamics simulations provide insights into the different binding modes and dynamic behaviour of the ligands within the pocket. Collectively, these findings define the structural basis of hMATE1 substrate specificity and shed light on its role in drug transport and drug-drug interactions.

PubMed: 41145429
DOI: 10.1038/s41467-025-64490-z

Experimental method

ELECTRON MICROSCOPY (2.95 Å)