9KNY
Cryo-EM structure of pyruvate-treated human mitochondrial pyruvate carrier in the IMS-open conformation at pH 8.0
Summary for 9KNY
| Entry DOI | 10.2210/pdb9kny/pdb |
| EMDB information | 62466 |
| Descriptor | Mitochondrial pyruvate carrier 2, Mitochondrial pyruvate carrier 1, MPC specific nanobody 1, ... (5 entities in total) |
| Functional Keywords | a membrane transporter complex with substrate, protein transport |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 3 |
| Total formula weight | 47984.99 |
| Authors | Shi, J.H.,Liang, J.M.,Ma, D. (deposition date: 2024-11-19, 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 Cited by 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: 40101766DOI: 10.1038/s41586-025-08873-8 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.4 Å) |
Structure validation
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