posted on 2021-10-19, 14:04authored byLiang Xu, Clyde F. Phelix, Liao Y. Chen
Pyruvate metabolism requires the
mitochondrial pyruvate carrier
(MPC) proteins to transport pyruvate from the intermembrane space
through the inner mitochondrial membrane to the mitochondrial matrix.
The lack of the atomic structures of MPC hampers the understanding
of the functional states of MPC and molecular interactions with the
substrate or inhibitor. Here, we develop the de novo models of human
MPC complexes and characterize the conformational dynamics of the
MPC heterodimer formed by MPC1 and MPC2 (MPC1/2) by computational
simulations. Our results reveal that functional MPC1/2 prefers to
adopt an inward-open conformation, with the carrier open to the matrix
side, whereas the outward-open states are less populated. The energy
barrier for pyruvate transport in MPC1/2 is low enough, and the inhibitor
UK5099 blocks the pyruvate transport by stably binding to MPC1/2.
Notably, consistent with experimental results, the MPC1 L79H mutation
significantly alters the conformations of MPC1/2 and thus fails for
substrate transport. However, the MPC1 R97W mutation seems to retain
the transport activity. The present de novo models of MPC complexes
provide structural insights into the conformational states of MPC
complexes and mechanistic understanding of interactions between the
substrate/inhibitor and MPC proteins.