Download MendeleyStructures and mechanism of human mitochondrial pyruvate carrier.
Liang, J., Shi, J., Song, A., Lu, M., Zhang, K., Xu, M., Huang, G., Lu, P., Wu, X., Ma, D.(2025) Nature
- PubMed: 40101766
- DOI: https://doi.org/10.1038/s41586-025-08873-8
- Primary Citation of Related Structures:
8YW6, 8YW8, 8YW9, 9KNW, 9KNX, 9KNY - 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 1,2 . 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 ?, a structure of pyruvate-treated MPC in occluded state at 3.7 ?, and two structures in matrix-facing state bound with the inhibitor UK5099 or an inhibitory nanobody on the matrix side at 3.2 ? and 3.0 ?, 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.
Organizational Affiliation:
Fudan University, Shanghai, China.
