2o2k
From Proteopedia
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Crystal Structure of the Activation Domain of Human Methionine Synthase Isoform/Mutant D963E/K1071N
Contents |
Overview
Human methionine synthase (hMS) is a multidomain cobalamin-dependent, enzyme that catalyses the conversion of homocysteine to methionine by, methyl group transfer. We report here the 1.6 A crystal structure of the, C-terminal activation domain of hMS. The structure is C-shaped with the, core comprising mixed alpha and beta regions, dominated by a twisted, antiparallel beta sheet with a beta-meander region. These features, including the positions of the active-site residues, are similar to the, activation domain of Escherichia coli cobalamin-dependent MS (MetH)., Structural and solution studies suggest a small proportion of hMS, activation domain exists in a dimeric form, which contrasts with the, monomeric form of the E. coli homologue. Fluorescence studies show that, human activation domain interacts with the FMN-binding domain of human, methionine synthase reductase (hMSR). This interaction is enhanced in the, presence of S-adenosyl-methionine. Binding of the D963E/K1071N mutant, activation domain to the FMN domain of MSR is weaker than with wild-type, activation domain. This suggests that one or both of the residues D963 and, K1071 are important in partner binding. Key differences in the sequences, and structures of hMS and MetH activation domains are recognized and, include a major reorientation of an extended 3(10)-containing loop in the, human protein. This structural alteration might reflect differences in, their respective reactivation complexes and/or potential for dimer, formation. The reported structure is a component of the multidomain hMS :, MSR complex, and represents an important step in understanding the impact, of clinical mutations and polymorphisms in this key electron transfer, complex.
Disease
Known diseases associated with this structure: Cleft lip/palate, susceptibility to OMIM:[156570], Down syndrome, susceptibility to OMIM:[156570], Methylcobalamin deficiency, cblG type OMIM:[156570], Neural tube defects, folate-sensitive, susceptibility to OMIM:[156570]
About this Structure
2O2K is a Single protein structure of sequence from Homo sapiens. Active as Methionine synthase, with EC number 2.1.1.13 Full crystallographic information is available from OCA.
Reference
Crystal structure and solution characterization of the activation domain of human methionine synthase., Wolthers KR, Toogood HS, Jowitt TA, Marshall KR, Leys D, Scrutton NS, FEBS J. 2007 Feb;274(3):738-50. PMID:17288554
Page seeded by OCA on Mon Nov 12 23:05:38 2007
