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PDBsum entry 1ca7
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Pro-1 of macrophage migration inhibitory factor functions as a catalytic base in the phenylpyruvate tautomerase activity.
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Authors
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J.B.Lubetsky,
M.Swope,
C.Dealwis,
P.Blake,
E.Lolis.
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Ref.
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Biochemistry, 1999,
38,
7346-7354.
[DOI no: ]
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PubMed id
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Abstract
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Macrophage migration inhibitory factor (MIF) is an important immunoregulatory
molecule with a unique ability to suppress the anti-inflammatory effects of
glucocorticoids. Although considered a cytokine, MIF possesses a
three-dimensional structure and active site similar to those of 4-oxalocrotonate
tautomerase and 5-carboxymethyl-2-hydroxymuconate isomerase. Moreover, a number
of catalytic activities have been defined for MIF. To gain insight into the role
of catalysis in the biological function of MIF, we have begun to characterize
the catalytic activities in more detail. Here we report the crystal structure of
MIF complexed with p-hydroxyphenylpyruvate, a substrate for the phenylpyruvate
tautomerase activity of MIF. The three binding sites for p-hydroxyphenylpyruvate
in the MIF trimer lie at the interface between two subunits. The substrate
interacts with Pro-1, Lys-32, and Ile-64 from one subunit and Tyr-95 and Asn-97
from an adjacent subunit. Pro-1 is positioned to function as a catalytic base.
There is no functional group that polarizes the alpha-carbonyl of the substrate
to weaken the adjacent C-H bond. Mutation of Pro-1 to glycine substantially
reduces the catalytic activity. The insertion of an alanine between Pro-1 and
Met-2 essentially abolishes activity. Structural studies of these mutants define
a source of the reduced activity and provide insight into the mechanism of the
catalytic reaction.
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