Structural Plasticity in the C-Terminal Region of Macrophage Migration Inhibitory Factor-2 Is Associated with an Induced Fit Mechanism for a Selective Inhibitor.
Biochemistry
; 57(26): 3599-3605, 2018 07 03.
Article
em En
| MEDLINE
| ID: mdl-29847104
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Fatores Inibidores da Migração de Macrófagos
/
Oxirredutases Intramoleculares
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Biochemistry
Ano de publicação:
2018
Tipo de documento:
Article