Macrophage migration inhibitory factor covalently complexed with phenethyl isothiocyanate

Abstract

PDB Reference: macrophage migration inhibitory factor, complex with phenethyl isothiocyanate, 4f2k.Macrophage migration inhibitory factor is irreversibly inhibited via covalent modification by phenethyl isothiocyanate, a naturally occurring compound with anti-inflammatory and anticancer properties. The structure of the modified protein obtained from X-ray diffraction data to 1.64 Å resolution is presented. The inhibitor sits within a deep hydrophobic pocket between subunits of the homotrimer and is highly ordered. The secondary structure of macrophage migratory inhibitory factor is unchanged by this modification, but there are significant rearrangements, including of the side-chain position of Tyr37 and the main chain of residues 31-34. These changes may explain the decreased binding of the modified protein to the receptor CD74. Together with the pocket, the areas of conformational change define specific targets for the design of more selective and potent inhibitors as potential therapeutics.

Structures of HIV-1 Env V1V2 with broadly neutralizing antibodies reveal commonalities that enable vaccine design

“…1a, b ). PGT145 was chosen for its high quaternary specificity and its broad and potent neutralization, and recognized V1V2 chimeras from two trimeric scaffolds, 1VH8 33 and 4F2K 34 .…”

Obacunone causes sustained expression of MKP‐1 thus inactivating p38 MAPK to suppress pro‐inflammatory mediators through intracellular MIF

“…These catalytic sites located near the hydrophobic pocket of MIF, which contains highly conserved amino acids known to be essential for MIF's pro‐inflammatory activity, also generally referred to as the pro‐inflammatory pocket because inhibition of these active sites reduces some of the pro‐inflammatory activities of MIF . Targeting MIF tautomerase activity by small‐molecule inhibitors has been regarded as an attractive strategy for inhibiting MIF pro‐inflammatory activity and attenuating its biologic activity in vitro and in vivo . Nevertheless, other researchers found that the immunological activity of MIF can be functionally dissociated from its tautomerase activity .…”

“…14 Targeting MIF tautomerase activity by smallmolecule inhibitors has been regarded as an attractive strategy for inhibiting MIF pro-inflammatory activity and attenuating its biologic activity in vitro and in vivo. 49,50 Nevertheless, other researchers found that the immunological activity of MIF can be functionally dissociated from its tautomerase activity. 51 In contrast to the tautomerase activity which is dispensable for the biological activity, the TPOR activity, mediated through a conserved Cys-57-Ala-Leu-Cys-60 (CXXC) motif, 33 plays a critical role in cellular redox homeostasis.…”

The Role of Isothiocyanates as Cancer Chemo-Preventive, Chemo-Therapeutic and Anti-Melanoma Agents

“…MIF is a pro-inflammatory cytokine with pro-tumourigenic, pro-angiogenic and anti-apoptotic properties. As such, it is involved in various inflammatory diseases, like rheumatoid arthritis and atherosclerosis, in addition to being implicated at different stages of tumour development, including proliferation and angiogenesis [57,58,59]. Consequently, a number of studies have supported the role of ITCs, especially sulforaphane (SFN), iberin (IBN), allyl-ITC (AITC), benzyl-ITC (BITC) and phenethyl-ITC (PEITC) (Figure 1), in cancer prevention and chemotherapy [60,61,62,63,64], topics which will be discussed in more detail below.…”