9MNZ

Cryo-EM structure of human MPC in complex with UK5099 in nanodiscs

Summary for 9MNZ

• Entry DOI: 10.2210/pdb9mnz/pdb
• EMDB information: 48444
• Descriptor: Fab_8D3_2 heavy chain, Nanobody, Mitochondrial pyruvate carrier 2, ... (7 entities in total)
• Functional Keywords: membrane transporter, transport protein-immune system complex, transport protein/immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 6
• Total formula weight: 159798.64

Authors

Zhang, J.,He, Z.,Feng, L. (deposition date: 2024-12-24, release date: 2025-03-05, Last modification date: 2025-06-04)

Primary citation

He, Z.,Zhang, J.,Xu, Y.,Fine, E.J.,Suomivuori, C.M.,Dror, R.O.,Feng, L.
Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
Nature, 641:250-257, 2025

PubMed Abstract: The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.

PubMed: 40044865
DOI: 10.1038/s41586-025-08667-y

Experimental method

ELECTRON MICROSCOPY (2.73 Å)