Domain alternation switches B12-dependent methionine synthase to the activation conformation

V. Bandarian, K. A. Pattridge, B. W. Lennon, D. P. Huddler, R. G. Matthews, M. L. Ludwig

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


B12-dependent methionine synthase (MetH) from Escherichia coli is a large modular protein that uses bound cobalamin as an intermediate methyl carrier. Major domain rearrangements have been postulated to explain how cobalamin reacts with three different substrates: homocysteine, methyltetrahydrofolate and S-adenosylmethionine (AdoMet). Here we describe the 3.0 Å structure of a 65 kDa C-terminal fragment of MetH that spans the cobalamin- and AdoMet-binding domains, arranged in a conformation suitable for the methyl transfer from AdoMet to cobalamin that occurs during activation. In the conversion to the activation conformation, a helical domain that capped the cofactor moves 26 Å and rotates by 63°, allowing formation of a new interface between cobalamin and the AdoMet-binding (activation) domain. Interactions with the MetH activation domain drive the cobalamin away from its binding domain in a way that requires dissociation of the axial cobalt ligand and, thereby, provide a mechanism for control of the distribution of enzyme conformations.

Original languageEnglish (US)
Pages (from-to)53-56
Number of pages4
JournalNature Structural Biology
Issue number1
StatePublished - 2002

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics


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