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- PDB-6peg: MIF with a allosteric inhibitor -

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Basic information

Entry
Database: PDB / ID: 6peg
TitleMIF with a allosteric inhibitor
ComponentsMacrophage migration inhibitory factor
KeywordsISOMERASE / Inhibitor / MIF / drug discovery
Function / homology
Function and homology information


: / positive regulation of myeloid leukocyte cytokine production involved in immune response / phenylpyruvate tautomerase / L-dopachrome isomerase / dopachrome isomerase activity / phenylpyruvate tautomerase activity / positive regulation of arachidonate secretion / cytokine receptor binding / negative regulation of myeloid cell apoptotic process / negative regulation of macrophage chemotaxis ...: / positive regulation of myeloid leukocyte cytokine production involved in immune response / phenylpyruvate tautomerase / L-dopachrome isomerase / dopachrome isomerase activity / phenylpyruvate tautomerase activity / positive regulation of arachidonate secretion / cytokine receptor binding / negative regulation of myeloid cell apoptotic process / negative regulation of macrophage chemotaxis / negative regulation of mature B cell apoptotic process / carboxylic acid metabolic process / positive regulation of lipopolysaccharide-mediated signaling pathway / positive regulation of chemokine (C-X-C motif) ligand 2 production / prostaglandin biosynthetic process / negative regulation of protein metabolic process / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of macrophage activation / chemoattractant activity / protein homotrimerization / negative regulation of DNA damage response, signal transduction by p53 class mediator / positive regulation of cAMP/PKA signal transduction / negative regulation of cellular senescence / positive regulation of phosphorylation / positive regulation of B cell proliferation / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / negative regulation of cell migration / cytokine activity / positive regulation of cytokine production / Cell surface interactions at the vascular wall / DNA damage response, signal transduction by p53 class mediator / positive regulation of fibroblast proliferation / positive regulation of tumor necrosis factor production / cellular senescence / protease binding / secretory granule lumen / vesicle / ficolin-1-rich granule lumen / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / inflammatory response / negative regulation of gene expression / innate immune response / positive regulation of cell population proliferation / Neutrophil degranulation / negative regulation of apoptotic process / cell surface / extracellular space / extracellular exosome / extracellular region / nucleoplasm / identical protein binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Macrophage migration inhibitory factor, conserved site / Macrophage migration inhibitory factor family signature. / Macrophage migration inhibitory factor / Macrophage migration inhibitory factor (MIF) / Macrophage Migration Inhibitory Factor / Macrophage Migration Inhibitory Factor / Tautomerase/MIF superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-4FQ / ACETATE ION / PHOSPHATE ION / Macrophage migration inhibitory factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsAsojo, O.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)2R44AR056908-02A1 United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Inhibition of Macrophage Migration Inhibitory Factor by a Chimera of Two Allosteric Binders.
Authors: Cirillo, P.F. / Asojo, O.A. / Khire, U. / Lee, Y. / Mootien, S. / Hegan, P. / Sutherland, A.G. / Peterson-Roth, E. / Ledizet, M. / Koski, R.A. / Anthony, K.G.
History
DepositionJun 20, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_radiation_wavelength.wavelength

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: Macrophage migration inhibitory factor
E: Macrophage migration inhibitory factor
F: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,58715
Polymers37,0653
Non-polymers1,52212
Water8,179454
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8940 Å2
ΔGint-102 kcal/mol
Surface area13260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.890, 67.890, 88.590
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 3 molecules DEF

#1: Protein Macrophage migration inhibitory factor / MIF / Glycosylation-inhibiting factor / GIF / L-dopachrome isomerase / L-dopachrome tautomerase / ...MIF / Glycosylation-inhibiting factor / GIF / L-dopachrome isomerase / L-dopachrome tautomerase / Phenylpyruvate tautomerase


Mass: 12355.056 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MIF, GLIF, MMIF / Production host: Escherichia coli (E. coli)
References: UniProt: P14174, phenylpyruvate tautomerase, L-dopachrome isomerase

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Non-polymers , 6 types, 466 molecules

#2: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-4FQ / 4-amino-5-hydroxy-6-[(E)-(3-{[3-(2-methylpropanoyl)pyrazolo[1,5-a]pyridin-2-yl]methyl}phenyl)diazenyl]naphthalene-1,3-disulfonic acid


Mass: 623.657 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H25N5O8S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 454 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.76 Å3/Da / Density % sol: 55.49 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 100microMolar 4048, 2M Ammonium sulfate, 4% isopropanol, 50 mM Tris pH 8.0, 12.5% Glycerol, 50mM sodium acetate Protein 100mg/ml MIF in 50mM citrate pH 5, 50microMolar 4048
PH range: 4.6-8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Feb 25, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→32.55 Å / Num. obs: 28255 / % possible obs: 99.8 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.042 / Net I/σ(I): 9.4
Reflection shellResolution: 2→2.05 Å / Redundancy: 6.3 % / Num. unique obs: 2013 / Rpim(I) all: 0.064 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1MIF

1mif


Resolution: 2→32.55 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.929 / SU B: 2.191 / SU ML: 0.065 / Cross valid method: THROUGHOUT / ESU R: 0.029 / ESU R Free: 0.028 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18765 1468 5.2 %RANDOM
Rwork0.14306 ---
obs0.14535 26728 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 10.16 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20 Å20 Å2
2--0.08 Å20 Å2
3----0.19 Å2
Refinement stepCycle: 1 / Resolution: 2→32.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2598 0 96 454 3148
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0142759
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172411
X-RAY DIFFRACTIONr_angle_refined_deg1.6431.6923756
X-RAY DIFFRACTIONr_angle_other_deg1.0321.6485646
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1885341
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.17222.366131
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.89715414
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8831516
X-RAY DIFFRACTIONr_chiral_restr0.0830.2351
X-RAY DIFFRACTIONr_gen_planes_refined0.010.023096
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02497
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.750.7781374
X-RAY DIFFRACTIONr_mcbond_other0.7470.7761372
X-RAY DIFFRACTIONr_mcangle_it1.0981.1531709
X-RAY DIFFRACTIONr_mcangle_other1.0981.1531710
X-RAY DIFFRACTIONr_scbond_it2.0271.0861385
X-RAY DIFFRACTIONr_scbond_other1.9351.0511366
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.8391.4852018
X-RAY DIFFRACTIONr_long_range_B_refined5.31612.0183321
X-RAY DIFFRACTIONr_long_range_B_other4.88510.9423157
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.169 105 -
Rwork0.117 1904 -
obs--99.01 %

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