PDBsum entry: 1ljt

Immune system

PDB id: 1ljt

Contents

Protein chains

114 a.a. *

Ligands

HDI ×3

Waters ×68

* Residue conservation analysis

PDB id:

1ljt

Name:

Immune system

Title:

Crystal structure of macrophage migration inhibitory factor complexed with (s,r)-3-(4-hydroxyphenyl)-4,5-dihydro-5- isoxazole-acetic acid methyl ester (iso-1)

Structure:

Macrophage migration inhibitory factor. Chain: a, b, c. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biol. unit:

Trimer (from PQS)

Resolution:

2.00Å R-factor: 0.237 R-free: 0.262

Authors:

J.B.Lubetsky,A.Dios,J.Han,B.Aljabari,B.Ruzsicska,R.Mitchell, E.Lolis,Y.Al-Abed

Key ref:

J.B.Lubetsky et al. (2002). The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J Biol Chem, 277, 24976-24982. PubMed id: 11997397 DOI: 10.1074/jbc.M203220200

Date:

22-Apr-02 Release date: 27-Nov-02

Protein chains

P14174  (MIF_HUMAN) -  Macrophage migration inhibitory factor

Seq: 115 a.a.

Struc: 114 a.a.

Enzyme reactions

• Enzyme class 2: E.C.5.3.2.1 - Phenylpyruvate tautomerase.
• Reaction: Keto-phenylpyruvate = enol-phenylpyruvate

Keto-phenylpyruvate (Bound ligand (Het Group name = HDI) matches with 61.00% similarity) = enol-phenylpyruvate

• Enzyme class 3: E.C.5.3.3.12 - L-dopachrome isomerase.

Pathway:

• Reaction: L-dopachrome = 5,6-dihydroxyindole-2-carboxylate

L-dopachrome (Bound ligand (Het Group name = HDI) matches with 55.00% similarity) = 5,6-dihydroxyindole-2-carboxylate

• Cofactor: Zinc

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

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular region (4 terms)
• Biological process: cell proliferation (31 terms)
• Biochemical function: chemoattractant activity (9 terms)

reference

DOI no: 10.1074/jbc.M203220200

J Biol Chem 277:24976-24982 (2002)

PubMed id: 11997397

The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents.

J.B.Lubetsky, A.Dios, J.Han, B.Aljabari, B.Ruzsicska, R.Mitchell, E.Lolis, Y.Al-Abed.

ABSTRACT

Macrophage migration inhibitory factor (MIF) is an immunoregulatory protein that is a potential therapeutic target for a number of inflammatory diseases. Evidence exists that an unexpected catalytic active site of MIF may have a biological function. To gain further insight into the role of the catalytic active site, a series of mutational, structural, and biological activity studies were performed. The insertion of an alanine between Pro-1 and Met-2 (PAM) abolishes a non-physiological catalytic activity, and this mutant is defective in the in vitro glucocorticoid counter-regulatory activity of MIF. The crystal structure of MIF complexed to (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), an inhibitor of MIF d-dopachrome tautomerase activity, reveals that ISO-1 binds to the same position of the active site as p-hydroxyphenylpyruvic acid, a substrate of MIF. ISO-1 inhibits several MIF biological activities, further establishing a role for the catalytic active site of MIF.

Selected figure(s)

Figure 6.
Fig. 6. Superposition of uncomplexed MIF and MIF·ISO-1. Backbone atom traces are shown for the trimer arrangements of uncomplexed MIF (black) and MIF·ISO-1 (gray). All atoms from the active site residues (Pro-1, Lys-32, Ile-64, Tyr-95, and Asn-97) are also displayed. This superposition reveals that there are no major conformational changes upon inhibitor binding. This figure was prepared with the program INSIGHTII (Molecular Simulations, Inc.).

Figure 7.
Fig. 7. Structure of ISO-1 and MIF. A, 2F[o] F[c] omit map at 1 for ISO-1 in the catalytic active site of MIF. The R-isomer is modeled in the electron density. The catalytic active site residues are displayed. B, schematic of the interactions between protein residues of MIF and ISO-1. All distances, with the exception of Pro-1A, represent hydrogen bonds. A series of aromatic-aromatic interactions, hydrogen bonds, and van der Waals contacts provide the binding energy for ISO-1. Pro-1A, Lys-32A, and Ile-64A are from one subunit, and Tyr-95C and Asn-97C are from an adjacent subunit. This figure was prepared with Bobscript (52) and ChemDraw (CambridgeSoft Corp., Cambridge, MA).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 24976-24982) copyright 2002.

Figures were selected by an automated process.