PDBsum entry 6b2c

Isomerase/isomerase inhibitor

PDB id: 6b2c

Contents

Protein chains

114 a.a.

Ligands

SO4

C9Y

Waters ×143

PDB id:

6b2c

Name:

Isomerase/isomerase inhibitor

Title:

Macrophage migration inhibitory factor in complex with a naphthyridinone inhibitor (4b)

Structure:

Macrophage migration inhibitory factor. Chain: a, b, c. Synonym: mif,glycosylation-inhibiting factor,gif,l-dopachrome isomerase,l-dopachrome tautomerase,phenylpyruvate tautomerase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mif, glif, mmif. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell: bl21.

Resolution:

2.00Å R-factor: 0.193 R-free: 0.222

Authors:

S.G.Krimmer,M.J.Robertson,W.L.Jorgensen

Key ref:

T.K.Dawson et al. (2017). Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor. ACS Med Chem Lett, 8, 1287-1291. PubMed id: 29259749

Date:

19-Sep-17 Release date: 03-Jan-18

Protein chains

P14174  (MIF_HUMAN) -  Macrophage migration inhibitory factor from Homo sapiens

Seq: 115 a.a.

Struc: 114 a.a.

Enzyme reactions

• Enzyme class 2: E.C.5.3.2.1 - phenylpyruvate tautomerase.
• Reaction: 3-phenylpyruvate = enol-phenylpyruvate
• Enzyme class 3: E.C.5.3.3.12 - L-dopachrome isomerase.

Pathway:

• Reaction: L-dopachrome = 5,6-dihydroxyindole-2-carboxylate
• Cofactor: Zn(2+)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

ACS Med Chem Lett 8:1287-1291 (2017)

PubMed id: 29259749

Adding a Hydrogen Bond May Not Help: Naphthyridinone vs Quinoline Inhibitors of Macrophage Migration Inhibitory Factor.

T.K.Dawson, P.Dziedzic, M.J.Robertson, J.A.Cisneros, S.G.Krimmer, A.S.Newton, J.Tirado-Rives, W.L.Jorgensen.

ABSTRACT

Coordination of the ammonium group of Lys32 in the active site of human macrophage migration inhibitory factor (MIF) using a 1,7-naphthyridin-8-one instead of a quinoline is investigated. Both gas- and aqueous-phase DFT calculations for model systems indicate potential benefits for the added hydrogen bond with the lactam carbonyl group, while FEP results are neutral. Three crystal structures are reported for complexes of MIF with3a,4a, and4b, which show that the desired hydrogen bond is formed with O-N distances of 2.8-3.0 Å. Compound4bis the most potent new MIF inhibitor withK_iandK_dvalues of 90 and 94 nM; it also has excellent aqueous solubility, 288 μg/mL. Consistent with the FEP results, the naphthyridinones are found to have similar potency as related quinolines in spite of the additional protein-ligand hydrogen bond.