Crystal structure of human D-dopachrome tautomerase, a homologue of macrophage migration inhibitory factor, at 1.54 A resolution

Biochemistry. 1999 Mar 16;38(11):3268-79. doi: 10.1021/bi982184o.

Abstract

D-Dopachrome tautomerase shares a low homologous amino acid sequence (33% homology) with the macrophage migration inhibitory factor (MIF) and possesses similar tautomerase activity as well. MIF is a cytokine involved in inflammatory reactions and immune responses. Whereas recent studies have identified MIF as a pituitary hormone and immunoregulator, much less is known about the structural basis of these physiological functions and the real significance of tautomerase activity. Therefore, interest in the structure-function relationship between D-dopachrome tautomerase and MIF has increased, especially with regard to inflammation and immune responses. We have determined the X-ray crystal structure of human D-dopachrome tautomerase at 1.54 A resolution. D-Dopachrome tautomerase folds to form a homotrimer that has extensive contact between subunits by intersubunit beta-sheets. Its overall topology and trimeric formations are similar to those of human MIF. The N-terminal proline is located at the bottom of a positively charged pocket in which the conformations of Lys32 and Ser63 are highly conserved. These positively charged properties are also seen in the active site pocket of human MIF, bacterial 5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI), and 4-oxalocrotonate tautomerase (4-OT). A detailed comparison of these structures revealed significant differences in the environment around the potential active site, the intersubunit contacts, and charge distribution on the molecular surface. It can be concluded that these features are related to the physiological role and tautomerase activity of MIF and D-dopachrome tautomerase. The present structural study could be helpful for designing effective inhibitors that modulate immunoregulatory and hormone-like effects.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Carbon-Carbon Double Bond Isomerases / chemistry
  • Cattle
  • Computer Simulation
  • Crystallization
  • Crystallography, X-Ray
  • Humans
  • Intramolecular Oxidoreductases / chemistry*
  • Isomerases / chemistry
  • Macrophage Migration-Inhibitory Factors / chemistry*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Rats
  • Sequence Homology, Amino Acid*

Substances

  • Macrophage Migration-Inhibitory Factors
  • 4-oxalocrotonate tautomerase
  • Isomerases
  • Intramolecular Oxidoreductases
  • Carbon-Carbon Double Bond Isomerases
  • 5-carboxymethyl-2-hydroxymuconate delta-isomerase
  • dopachrome isomerase

Associated data

  • PDB/1DPT
  • PDB/R1DPTSF