Structure of the ATP-driven methyl-coenzyme M reductase activation complex

Fidel Ramírez-Amador, Sophia Paul, Anuj Kumar, Christian Lorent, Sebastian Keller, Stefan Bohn, Thinh Nguyen, Stefano Lometto, Dennis Vlegels, Jörg Kahnt, Darja Deobald, Frank Abendroth, Olalla Vázquez, Georg Hochberg, Silvan Scheller, Sven T. Stripp and Jan Michael Schuller ()
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Fidel Ramírez-Amador: Philipps-University Marburg
Sophia Paul: Philipps-University Marburg
Anuj Kumar: Philipps-University Marburg
Christian Lorent: Institute of Chemistry
Sebastian Keller: Aalto University
Stefan Bohn: Helmholtz Munich
Thinh Nguyen: Aalto University
Stefano Lometto: Max Planck Institute for Terrestrial Microbiology and Department of Biology, Philipps-University Marburg
Dennis Vlegels: Max Planck Institute for Terrestrial Microbiology and Department of Biology, Philipps-University Marburg
Jörg Kahnt: Max Planck Institute for Terrestrial Microbiology and Department of Biology, Philipps-University Marburg
Darja Deobald: Helmholtz Centre for Environmental Research (UFZ)
Frank Abendroth: Philipps-University Marburg
Olalla Vázquez: Philipps-University Marburg
Georg Hochberg: Philipps-University Marburg
Silvan Scheller: Aalto University
Sven T. Stripp: Institute of Chemistry
Jan Michael Schuller: Philipps-University Marburg

Nature, 2025, vol. 642, issue 8068, 814-821

Abstract: Abstract Methyl-coenzyme M reductase (MCR) is the enzyme responsible for nearly all biologically generated methane1. Its active site comprises coenzyme F430, a porphyrin-based cofactor with a central nickel ion that is active exclusively in the Ni(I) state2,3. How methanogenic archaea perform the reductive activation of F430 represents a major gap in our understanding of one of the most ancient bioenergetic systems in nature. Here we purified and characterized the MCR activation complex from Methanococcus maripaludis. McrC, a small subunit encoded in the mcr operon, co-purifies with the methanogenic marker proteins Mmp7, Mmp17, Mmp3 and the A2 component. We demonstrated that this complex can activate MCR in vitro in a strictly ATP-dependent manner, enabling the formation of methane. In addition, we determined the cryo-electron microscopy structure of the MCR activation complex exhibiting different functional states with local resolutions reaching 1.8–2.1 Å. Our data revealed three complex iron–sulfur clusters that formed an electron transfer pathway towards F430. Topology and electron paramagnetic resonance spectroscopy analyses indicate that these clusters are similar to the [8Fe-9S-C] cluster, a maturation intermediate of the catalytic cofactor in nitrogenase. Altogether, our findings offer insights into the activation mechanism of MCR and prospects on the early evolution of nitrogenase.

Date: 2025
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DOI: 10.1038/s41586-025-08890-7

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