9giy

Structure of the human mitochondrial pyruvate carrier inhibited by mitoglitazone

spinqualitylabelsall models 9giy, resolution 3.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9giy is a 3 chain structure with sequence from Escherichia coli K-12, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.79Å Ligands: A1IMZ, LO7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MPC1L_HUMAN Mediates the uptake of pyruvate into mitochondria. Publication Abstract from PubMed 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 DeltapH-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. Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier.,Sichrovsky M, Lacabanne D, Ruprecht JJ, Rana JJ, Stanik K, Dionysopoulou M, Sowton AP, King MS, Jones SA, Cooper L, Hardwick SW, Paris G, Chirgadze DY, Ding S, Fearnley IM, Palmer SM, Pardon E, Steyaert J, Leone V, Forrest LR, Tavoulari S, Kunji ERS Sci Adv. 2025 Apr 18;11(16):eadw1489. doi: 10.1126/sciadv.adw1489. Epub 2025 Apr , 18. PMID:40249800 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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