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Biochemistry. 2018 Jul 3;57(26):3599-3605. doi: 10.1021/acs.biochem.8b00344. Epub 2018 Jun 12.

Structural Plasticity in the C-Terminal Region of Macrophage Migration Inhibitory Factor-2 Is Associated with an Induced Fit Mechanism for a Selective Inhibitor.

Author information

1
Department of Pharmacology , Yale School of Medicine , New Haven , Connecticut 06510 , United States.
2
Internal Medicine , Yale School of Medicine , New Haven , Connecticut 06510 , United States.
3
Yale Cancer Center , Yale School of Medicine , New Haven , Connecticut 06510 , United States.

Abstract

We report the first reversible and selective small molecule inhibitor of pro-inflammatory protein macrophage migration inhibitory factor-2 (also known as MIF-2 or d-DT). 4-(3-Carboxyphenyl)-2,5-pyridinedicarboxylic acid (4-CPPC) shows competitive binding with a 13-fold selectivity for human MIF-2 versus human MIF-1. The crystal structure of MIF-2 complexed with 4-CPPC reveals an induced fit mechanism that is not observed in the numerous MIF-1/inhibitor complexes. Crystallographic analysis demonstrates the structural source of 4-CPPC binding and selectivity for MIF-2. 4-CPPC can be employed to reveal previously unrecognized functions of MIF-1 in biological systems in which both MIF-1 and MIF-2 are expressed, to improve our knowledge of the MIF family of proteins, and to provide new mechanistic insights that can be utilized for the development of potent and selective pharmacological modulators of MIF-2.

PMID:
29847104
PMCID:
PMC6123015
DOI:
10.1021/acs.biochem.8b00344
[Indexed for MEDLINE]
Free PMC Article

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