8YW8

Cryo-EM structure of human mitochondrial pyruvate carrier in complex with the inhibitor UK5099

Summary for 8YW8

• Entry DOI: 10.2210/pdb8yw8/pdb
• EMDB information: 39625
• Descriptor: Mitochondrial pyruvate carrier 2, MPC specific nanobody 1, Mitochondrial pyruvate carrier 1, ... (5 entities in total)
• Functional Keywords: mitochondrial pyruvate carrier, mpc, pyruvate transport, protein transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 47762.66

Authors

Shi, J.H.,Liang, J.M.,Ma, D. (deposition date: 2024-03-30, release date: 2025-03-12, Last modification date: 2025-05-14)

Primary citation

Liang, J.,Shi, J.,Song, A.,Lu, M.,Zhang, K.,Xu, M.,Huang, G.,Lu, P.,Wu, X.,Ma, D.
Structures and mechanism of the human mitochondrial pyruvate carrier.
Nature, 641:258-265, 2025

PubMed Abstract: Mitochondrial pyruvate carrier (MPC) is a mitochondrial inner membrane protein complex essential for uptake of pyruvate into matrix as the primary carbon source for tricarboxylic acid (TCA) cycle. Here, we report six cryo-EM structures of human MPC in three different states: three structures obtained at different conditions in intermembrane space (IMS)-open state with highest resolution of 3.2 Å, a structure of pyruvate-treated MPC in occluded state at 3.7 Å, and two structures in matrix-facing state bound with the inhibitor UK5099 or an inhibitory nanobody on the matrix side at 3.2 Å and 3.0 Å, respectively. MPC is assigned into a heterodimer consisting of MPC1 and MPC2, with the transmembrane domain adopting pseudo-C2-symmetry. Approximate rigid body movements occur between the IMS-open state and the occluded state, while structural changes primarily on the matrix side facilitate the transition between the occluded state and the matrix-facing state, revealing the alternating access mechanism during pyruvate transport. In the UK5099-bound structure, the inhibitor fits well and interacts extensively with a pocket that opens to the matrix side. Our findings provide important insights into the mechanisms underlying MPC-mediated substrate transport, and the recognition and inhibition by UK5099, which will facilitate future drug development targeting MPC.

PubMed: 40101766
DOI: 10.1038/s41586-025-08873-8

Experimental method

ELECTRON MICROSCOPY (3.17 Å)