4WR8
Macrophage Migration Inhibitory Factor in complex with a biaryltriazole inhibitor (3b-180)
Summary for 4WR8
| Entry DOI | 10.2210/pdb4wr8/pdb |
| Related | 4WRB |
| Descriptor | Macrophage migration inhibitory factor, SULFATE ION, 4-[4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl]phenol, ... (5 entities in total) |
| Functional Keywords | cd74 binding, tautomerase, inhibitor, complex, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 18 |
| Total formula weight | 229281.14 |
| Authors | Robertson, M.J.,Baxter, R.H.G.,Jorgensen, W.L. (deposition date: 2014-10-23, release date: 2015-03-11, Last modification date: 2023-12-27) |
| Primary citation | Dziedzic, P.,Cisneros, J.A.,Robertson, M.J.,Hare, A.A.,Danford, N.E.,Baxter, R.H.,Jorgensen, W.L. Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor. J.Am.Chem.Soc., 137:2996-3003, 2015 Cited by PubMed Abstract: Optimization is reported for biaryltriazoles as inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF), a proinflammatory cytokine associated with numerous inflammatory diseases and cancer. A combined approach was taken featuring organic synthesis, enzymatic assaying, crystallography, and modeling including free-energy perturbation (FEP) calculations. X-ray crystal structures for 3a and 3b bound to MIF are reported and provided a basis for the modeling efforts. The accommodation of the inhibitors in the binding site is striking with multiple hydrogen bonds and aryl-aryl interactions. Additional modeling encouraged pursuit of 5-phenoxyquinolinyl analogues, which led to the very potent compound 3s. Activity was further enhanced by addition of a fluorine atom adjacent to the phenolic hydroxyl group as in 3w, 3z, 3aa, and 3bb to strengthen a key hydrogen bond. It is also shown that physical properties of the compounds can be modulated by variation of solvent-exposed substituents. Several of the compounds are likely the most potent known MIF tautomerase inhibitors; the most active ones are more than 1000-fold more active than the well-studied (R)-ISO-1 and more than 200-fold more active than the chromen-4-one Orita-13. PubMed: 25697265DOI: 10.1021/ja512112j PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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