3IJG

Macrophage Migration Inhibitory Factor (MIF) Bound to the (R)-Stereoisomer of AV1013

Summary for 3IJG

• Entry DOI: 10.2210/pdb3ijg/pdb
• Related: 3IJJ
• Descriptor: Macrophage migration inhibitory factor, CHLORIDE ION, (2R)-2-amino-1-[2-(1-methylethyl)pyrazolo[1,5-a]pyridin-3-yl]propan-1-one, ... (4 entities in total)
• Functional Keywords: allosteric binding, cytokine, immune response, inflammatory response, innate immunity, isomerase, phosphoprotein, secreted
• Biological source: Homo sapiens (human)
• Cellular location: Secreted : P14174
• Total number of polymer chains: 3
• Total formula weight: 37650.99

Authors

Crichlow, G.V.,Cho, Y.,Lolis, E.J. (deposition date: 2009-08-04, release date: 2010-06-16, Last modification date: 2023-09-06)

Primary citation

Cho, Y.,Crichlow, G.V.,Vermeire, J.J.,Leng, L.,Du, X.,Hodsdon, M.E.,Bucala, R.,Cappello, M.,Gross, M.,Gaeta, F.,Johnson, K.,Lolis, E.J.
Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast.
Proc.Natl.Acad.Sci.USA, 107:11313-11318, 2010

PubMed Abstract: AV411 (ibudilast; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) is an antiinflammatory drug that was initially developed for the treatment of bronchial asthma but which also has been used for cerebrovascular and ocular indications. It is a nonselective inhibitor of various phosphodiesterases (PDEs) and has varied antiinflammatory activity. More recently, AV411 has been studied as a possible therapeutic for the treatment of neuropathic pain and opioid withdrawal through its actions on glial cells. As described herein, the PDE inhibitor AV411 and its PDE-inhibition-compromised analog AV1013 inhibit the catalytic and chemotactic functions of the proinflammatory protein, macrophage migration inhibitory factor (MIF). Enzymatic analysis indicates that these compounds are noncompetitive inhibitors of the p-hydroxyphenylpyruvate (HPP) tautomerase activity of MIF and an allosteric binding site of AV411 and AV1013 is detected by NMR. The allosteric inhibition mechanism is further elucidated by X-ray crystallography based on the MIF/AV1013 binary and MIF/AV1013/HPP ternary complexes. In addition, our antibody experiments directed against MIF receptors indicate that CXCR2 is the major receptor for MIF-mediated chemotaxis of peripheral blood mononuclear cells.

PubMed: 20534506
DOI: 10.1073/pnas.1002716107

Experimental method

X-RAY DIFFRACTION (1.7 Å)