Domain alternation switches B(12)-dependent methionine synthase to the activation conformation

Nat Struct Biol. 2002 Jan;9(1):53-6. doi: 10.1038/nsb738.


B(12)-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 A 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 A and rotates by 63 degrees, 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / chemistry*
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism*
  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Activation
  • Escherichia coli / enzymology*
  • Models, Molecular
  • Movement
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • S-Adenosylmethionine / metabolism
  • Vitamin B 12 / metabolism


  • Peptide Fragments
  • S-Adenosylmethionine
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Vitamin B 12

Associated data

  • PDB/1K7Y
  • PDB/1K98