9GIX

Structure of the human mitochondrial pyruvate carrier in the apo-state

Summary for 9GIX

• Entry DOI: 10.2210/pdb9gix/pdb
• Related: 9GIV 9GIW 9GIY
• EMDB information: 51380
• Descriptor: Mitochondrial pyruvate carrier 1-like protein, Mitochondrial pyruvate carrier 2, MBP-nanobody,Maltose/maltodextrin-binding periplasmic protein (3 entities in total)
• Functional Keywords: transporter slc54 pyruvate uk5099-derivative, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 86556.32

Authors

Sichrovsky, M.,Lacabanne, D.,Ruprecht, J.J.,Rana, J.J.,Stanik, K.,Dionysopoulou, M.,Sowton, A.P.,King, M.S.,Jones, S.,Cooper, L.,Hardwick, S.W.,Paris, G.,Chirgadze, D.Y.,Ding, S.,Fearnley, I.M.,Palmer, S.,Pardon, E.,Steyaert, J.,Leone, V.,Forrest, L.R.,Tavoulari, S.,Kunji, E.R.S. (deposition date: 2024-08-19, release date: 2025-05-07)

Primary citation

Sichrovsky, M.,Lacabanne, D.,Ruprecht, J.J.,Rana, J.J.,Stanik, K.,Dionysopoulou, M.,Sowton, A.P.,King, M.S.,Jones, S.A.,Cooper, L.,Hardwick, S.W.,Paris, G.,Chirgadze, D.Y.,Ding, S.,Fearnley, I.M.,Palmer, S.M.,Pardon, E.,Steyaert, J.,Leone, V.,Forrest, L.R.,Tavoulari, S.,Kunji, E.R.S.
Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.
Sci Adv, 11:eadw1489-eadw1489, 2025

PubMed Abstract: The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.

PubMed: 40249800
DOI: 10.1126/sciadv.adw1489

Experimental method

ELECTRON MICROSCOPY (3.65 Å)