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Angew Chem Int Ed Engl. 2018 Jun 11;57(24):7116-7119. doi: 10.1002/anie.201803191. Epub 2018 May 9.

Nanosecond Dynamics Regulate the MIF-Induced Activity of CD74.

Author information

1
Department of Pharmacology, School of Medicine, Yale University, New Haven, CT, 06510, USA.
2
Department of Chemistry, Yale University, New Haven, CT, 06520, USA.
3
School of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia.
4
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA.
5
Department of Pediatrics, Yale School of Medicine, New Haven, CT, 06510, USA.
6
Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06510, USA.
7
Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06510, USA.
8
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA.

Abstract

Macrophage migration inhibitory factor (MIF) activates CD74, which leads to severe disorders including inflammation, autoimmune diseases and cancer under pathological conditions. Molecular dynamics (MD) simulations up to one microsecond revealed dynamical correlation between a residue located at the opening of one end of the MIF solvent channel, previously thought to be a consequence of homotrimerization, and residues in a distal region responsible for CD74 activation. Experiments verified the allosteric regulatory site and identified a pathway to this site via the MIF β-strands. The reported findings provide fundamental insights on a dynamic mechanism that controls the MIF-induced activation of CD74.

KEYWORDS:

MIF; allosteric sites; long-range communication; protein dynamics

PMID:
29669180
PMCID:
PMC6282165
DOI:
10.1002/anie.201803191
[Indexed for MEDLINE]
Free PMC Article

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