6FOE

BaxB01 Fab fragment

Summary for 6FOE

• Entry DOI: 10.2210/pdb6foe/pdb
• Descriptor: Fab BaxB01 heavy chain, Fab BaxB01 light chain (3 entities in total)
• Functional Keywords: igg derived fab, macrophage migration inhibitory factor, oxmif form, peptide binding protein, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 94609.49

Authors

Hollerweger, J.,Schinagl, A.,Kerschbaumer, R.J.,Scheiflinger, F.,Thiele, M.,Goettig, P.,Brandstetter, H. (deposition date: 2018-02-07, release date: 2018-02-28, Last modification date: 2024-01-17)

Primary citation

Schinagl, A.,Kerschbaumer, R.J.,Sabarth, N.,Douillard, P.,Scholz, P.,Voelkel, D.,Hollerweger, J.C.,Goettig, P.,Brandstetter, H.,Scheiflinger, F.,Thiele, M.
Role of the Cysteine 81 Residue of Macrophage Migration Inhibitory Factor as a Molecular Redox Switch.
Biochemistry, 57:1523-1532, 2018

PubMed Abstract: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory and tumor-promoting cytokine that occurs in two redox-dependent immunologically distinct conformational isoforms. The disease-related structural isoform of MIF (oxMIF) can be specifically and predominantly detected in the circulation of patients with inflammatory diseases and in tumor tissue, whereas the ubiquitously expressed isoform of MIF (redMIF) is abundantly expressed in healthy and diseased subjects. In this article, we report that cysteine 81 within MIF serves as a "switch cysteine" for the conversion of redMIF to oxMIF. Modulating cysteine 81 by thiol reactive agents leads to significant structural rearrangements of the protein, resulting in a decreased β-sheet content and an increased random coil content, but maintaining the trimeric quaternary structure. This conformational change in the MIF molecule enables binding of oxMIF-specific antibodies BaxB01 and BaxM159, which showed beneficial activity in animal models of inflammation and cancer. Crystal structure analysis of the MIF-derived EPCALCS peptide, bound in its oxMIF-like conformation by the Fab fragment of BaxB01, revealed that this peptide adopts a curved conformation, making the central thiol protein oxidoreductase motif competent to undergo disulfide shuffling. We conclude that redMIF might reflect a latent zymogenic form of MIF, and formation of oxMIF leads to a physiologically relevant, i.e., enzymatically active, state.

PubMed: 29412660
DOI: 10.1021/acs.biochem.7b01156

Experimental method

X-RAY DIFFRACTION (2.6 Å)