InterPro domain: IPR003726

The homocysteine (Hcy) binding domain is an ~300-residue module which is found in a set of enzymes involved in alkyl transfer to thiols:

• Prokaryotic and eukaryotic B12-dependent methionine synthase (MetH) (EC 2.1.1.13), a large, modular protein that catalyses the transfer of a methyl group from methyltetrahydrofolate (CH3-H4folate) to Hcy to form methionine, using cobalamin as an intermediate methyl carrier.
• Mammalian betaine-homocysteine S-methyltransferase (BHMT) (EC 2.1.1.5). It catalyzes the transfer of a methyl group from glycine betaine to Hcy, forming methionine and dimethylglycine.
• Plant selenocysteine methyltransferase (EC 2.1.1.-).
• Plant and fungal AdoMet homocysteine S-methyltransferases (EC 2.1.1.10).

The Hcy-binding domain utilises a Zn(Cys)3 cluster to bind and activate Hcy. It has been shown to form a (beta/alpha)8 barrel. The Hcy binding domain barrel is distorted to form the metal- and substrate-binding sites. To accommodate the substrate, strands 1 and 2 of the barrel are loosely joined by nonclassic hydrogen bonds; to accommodate the metal, strands 6 and 8 are drawn together and strand 7 is extruded from the end of the barrel. The cysteines ligating the catalytic zinc atom are located at the C-terminal ends of strands 6 and 8 [ 1 , 2 ].

1. Betaine-homocysteine methyltransferase: zinc in a distorted barrel. Structure 10, 1159-71
2. Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase. Proc. Natl. Acad. Sci. U.S.A. 101, 3729-36