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Dissecting the conformational complexity and mechanism of a bacterial heme transporter

MPG-Autoren
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Wu,  Di       
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Mehdipour,  Ahmad Reza       
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;
Center for Molecular Modeling (CMM), Ghent University, Zwijnaarde, Belgium;

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Finke,  Franziska       
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Groh,  Roan René
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Grund,  Tamara Natascha       
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Reichhart,  Thomas M. B.       
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Zimmermann,  Rita
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Welsch,  Sonja       
Central Electron Microscopy Facility, Max Planck Institute of Biophysics, Max Planck Society;

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Hummer,  Gerhard       
Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society;
Institute of Biophysics, Goethe University Frankfurt, Frankfurt/Main, Germany;

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Safarian,  Schara       
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;
Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand;
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt/Main, Germany;

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Zitation

Wu, D., Mehdipour, A. R., Finke, F., Goojani, H. G., Groh, R. R., Grund, T. N., et al. (2023). Dissecting the conformational complexity and mechanism of a bacterial heme transporter. Nature Chemical Biology, 19(8), 992-1003. doi:10.1038/s41589-023-01314-5.


Zitierlink: https://hdl.handle.net/21.11116/0000-000D-09B9-9
Zusammenfassung
Iron-bound cyclic tetrapyrroles (hemes) are redox-active cofactors in bioenergetic enzymes. However, the mechanisms of heme transport and insertion into respiratory chain complexes remain unclear. Here, we used cellular, biochemical, structural and computational methods to characterize the structure and function of the heterodimeric bacterial ABC transporter CydDC. We provide multi-level evidence that CydDC is a heme transporter required for functional maturation of cytochrome bd, a pharmaceutically relevant drug target. Our systematic single-particle cryogenic-electron microscopy approach combined with atomistic molecular dynamics simulations provides detailed insight into the conformational landscape of CydDC during substrate binding and occlusion. Our simulations reveal that heme binds laterally from the membrane space to the transmembrane region of CydDC, enabled by a highly asymmetrical inward-facing CydDC conformation. During the binding process, heme propionates interact with positively charged residues on the surface and later in the substrate-binding pocket of the transporter, causing the heme orientation to rotate 180°.