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结构洞察人类线粒体丙酮酸载体复合物。

Structural Insights into the Human Mitochondrial Pyruvate Carrier Complexes.

机构信息

Department of Physics and Astronomy, The University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, United States.

Department of Integrative Biology, The University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, United States.

出版信息

J Chem Inf Model. 2021 Nov 22;61(11):5614-5625. doi: 10.1021/acs.jcim.1c00879. Epub 2021 Oct 19.

Abstract

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.

摘要

丙酮酸代谢需要线粒体丙酮酸载体(MPC)蛋白将丙酮酸从膜间空间通过线粒体内膜转运到线粒体基质。缺乏 MPC 的原子结构阻碍了对 MPC 功能状态的理解以及与底物或抑制剂的分子相互作用。在这里,我们通过计算模拟开发了人 MPC 复合物的从头模型,并对由 MPC1 和 MPC2(MPC1/2)形成的 MPC 异二聚体的构象动力学进行了表征。我们的结果表明,功能性 MPC1/2 优先采用内向开放构象,载体向基质侧开放,而外向开放状态较少。MPC1/2 中丙酮酸转运的能量障碍足够低,抑制剂 UK5099 通过稳定结合 MPC1/2 阻止丙酮酸转运。值得注意的是,与实验结果一致,MPC1 L79H 突变显著改变了 MPC1/2 的构象,因此无法进行底物转运。然而,MPC1 R97W 突变似乎保留了转运活性。MPC 复合物的现有从头模型为 MPC 复合物的构象状态提供了结构见解,并深入了解了底物/抑制剂与 MPC 蛋白之间的相互作用机制。

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