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- PDB-7xtx: High resolution crystal structure of human macrophage migration i... -

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Basic information

Entry
Database: PDB / ID: 7xtx
TitleHigh resolution crystal structure of human macrophage migration inhibitory factor in complex with methotrexate
ComponentsMacrophage migration inhibitory factor
KeywordsCYTOKINE/INHIBITOR / methotrexate / cytokine-inhibitor complex
Function / homology
Function and homology information


positive regulation of prostaglandin secretion involved in immune response / positive regulation of myeloid leukocyte cytokine production involved in immune response / dopachrome isomerase activity / phenylpyruvate tautomerase / L-dopachrome isomerase / 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 prostaglandin secretion involved in immune response / positive regulation of myeloid leukocyte cytokine production involved in immune response / dopachrome isomerase activity / phenylpyruvate tautomerase / L-dopachrome isomerase / 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 / regulation of macrophage activation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / protein homotrimerization / chemoattractant activity / 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 / DNA damage response, signal transduction by p53 class mediator / negative regulation of cell migration / cytokine activity / positive regulation of cytokine production / Cell surface interactions at the vascular wall / 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 / innate immune response / negative regulation of gene expression / 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 / cytosol / cytoplasm
Similarity search - Function
Macrophage migration inhibitory factor, conserved site / Macrophage migration inhibitory factor family signature. / Macrophage migration inhibitory factor / Macrophage migration inhibitory factor (MIF) / Tautomerase/MIF superfamily
Similarity search - Domain/homology
ISOPROPYL ALCOHOL / Chem-MT1 / Macrophage migration inhibitory factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.28 Å
AuthorsSugishima, K. / Noguchi, K. / Yohda, M. / Odaka, M. / Matsumura, H.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)19K07011 Japan
CitationJournal: To Be Published
Title: Identification of methotrexate as an inhibitor of macrophage migration inhibitory factor by high-resolution crystal structure analysis
Authors: Sugishima, K. / Kariya, Y. / Ezawa, T. / Nagatoishi, S. / Tsumoto, K. / Shigeta, Y. / Noguchi, K. / Yohda, M. / Odaka, M. / Wakui, H. / Matsumura, H.
History
DepositionMay 18, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 24, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Macrophage migration inhibitory factor
B: Macrophage migration inhibitory factor
C: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,76822
Polymers37,0653
Non-polymers1,70319
Water5,909328
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10090 Å2
ΔGint-61 kcal/mol
Surface area14040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.520, 68.284, 88.477
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 3 molecules ABC

#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 , 5 types, 347 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL


Mass: 60.095 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#5: Chemical ChemComp-MT1 / N-(4-{[(2,4-DIAMINOPTERIDIN-1-IUM-6-YL)METHYL](METHYL)AMINO}BENZOYL)-L-GLUTAMIC ACID / METHOTREXATE PROTONATED AT N1


Mass: 455.447 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23N8O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: chemotherapy*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 328 / 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: 2.75 Å3/Da / Density % sol: 55.3 %
Crystal growTemperature: 283 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 2.0 M Ammonium sulfate 0.1 M Tris-HCl (pH 8.0) 4 % isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Dec 2, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.28→50 Å / Num. obs: 104194 / % possible obs: 98.3 % / Redundancy: 6.7 % / Biso Wilson estimate: 14.82 Å2 / CC1/2: 1 / Net I/σ(I): 27.4
Reflection shellResolution: 1.28→1.33 Å / Num. unique obs: 10126 / CC1/2: 0.73 / % possible all: 96.7

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5J7Q

5j7q


Resolution: 1.28→34.14 Å / SU ML: 0.1219 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 17.3821 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.188 5339 5.13 %
Rwork0.17 98770 -
obs0.1709 104109 98.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 17.55 Å2
Refinement stepCycle: LAST / Resolution: 1.28→34.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2601 0 109 328 3038
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00532908
X-RAY DIFFRACTIONf_angle_d0.80143967
X-RAY DIFFRACTIONf_chiral_restr0.0875429
X-RAY DIFFRACTIONf_plane_restr0.0059522
X-RAY DIFFRACTIONf_dihedral_angle_d7.3731629
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.28-1.290.27011630.27212849X-RAY DIFFRACTION85.91
1.29-1.310.27811780.24643210X-RAY DIFFRACTION97.89
1.31-1.320.25391810.23683316X-RAY DIFFRACTION99.29
1.32-1.340.24261780.23583297X-RAY DIFFRACTION99.37
1.34-1.360.22271520.22053310X-RAY DIFFRACTION99.23
1.36-1.380.21521710.20973287X-RAY DIFFRACTION98.77
1.38-1.40.23471920.20963281X-RAY DIFFRACTION99.09
1.4-1.420.24121610.19993299X-RAY DIFFRACTION98.89
1.42-1.440.1951850.19443271X-RAY DIFFRACTION98.63
1.44-1.460.2341680.18593288X-RAY DIFFRACTION98.83
1.46-1.490.19151480.17823301X-RAY DIFFRACTION98.26
1.49-1.520.16851910.17273270X-RAY DIFFRACTION98.13
1.52-1.540.20061960.16673249X-RAY DIFFRACTION98.26
1.54-1.580.17881750.17073284X-RAY DIFFRACTION97.91
1.58-1.610.16961940.16543279X-RAY DIFFRACTION98.83
1.61-1.650.19161690.15723275X-RAY DIFFRACTION98.29
1.65-1.690.16831820.15523298X-RAY DIFFRACTION98.36
1.69-1.740.15581750.163280X-RAY DIFFRACTION98.04
1.74-1.790.20871930.15653232X-RAY DIFFRACTION97.69
1.79-1.840.18831930.16123279X-RAY DIFFRACTION97.75
1.84-1.910.16161720.15643280X-RAY DIFFRACTION97.79
1.91-1.990.1642170.15893237X-RAY DIFFRACTION97.76
1.99-2.080.17791780.1593291X-RAY DIFFRACTION97.61
2.08-2.190.17281860.15763303X-RAY DIFFRACTION97.79
2.19-2.320.15531400.1583348X-RAY DIFFRACTION98.06
2.32-2.50.19081750.17583358X-RAY DIFFRACTION99.05
2.5-2.750.20271790.17943390X-RAY DIFFRACTION99.69
2.75-3.150.2071800.17893425X-RAY DIFFRACTION99.97
3.15-3.970.16581890.15763469X-RAY DIFFRACTION99.95
3.97-34.140.20041780.16493514X-RAY DIFFRACTION97.23

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