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Abstract:
Methanogenic archaea inhabiting anaerobic environments play a crucial role in the
global biogeochemical material cycle. The most universal electrogenic reaction of their
methane-producing energy metabolism is catalyzed by N5-methyl-tetrahydromethanopterin:
coenzyme M methyltransferase (MtrABCDEFGH), which couples the vectorial Na+
transport with a methyl transfer between the one-carbon carriers tetrahydromethano-
pterin and coenzyme M via a vitamin B12 derivative (cobamide) as prosthetic group.
We present the 2.08 Å cryo-EM structure of Mtr(ABCDEFG)3 composed of the cen-
tral Mtr(ABFG)3 stalk symmetrically flanked by three membrane-spanning MtrCDE
globes. Tetraether glycolipids visible in the map fill gaps inside the multisubunit complex.
Putative coenzyme M and Na+ were identified inside or in a side-pocket of a cytoplas-
mic cavity formed within MtrCDE. Its bottom marks the gate of the transmembrane
pore occluded in the cryo-EM map. By integrating Alphafold2 information, function-
ally competent MtrA–MtrH and MtrA–MtrCDE subcomplexes could be modeled and
thus the methyl-tetrahydromethanopterin demethylation and coenzyme M methyla-
tion half-reactions structurally described. Methyl-transfer-driven Na+ transport is pro-
posed to be based on a strong and weak complex between MtrCDE and MtrA carrying
vitamin B12, the latter being placed at the entrance of the cytoplasmic MtrCDE cavity.
Hypothetically, strongly attached methyl-cob(III)amide (His-on) carrying MtrA induces
an inward-facing conformation, Na+ flux into the membrane protein center and finally
coenzyme M methylation while the generated loosely attached (or detached) MtrA car-
rying cob(I)amide (His-off) induces an outward-facing conformation and an extracellular
Na+ outflux. Methyl-cob(III)amide (His-on) is regenerated in the distant active site of
the methyl-tetrahydromethanopterin binding MtrH implicating a large-scale shuttling
movement of the vitamin B12-carrying domain.
