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- PDB-4wr8: Macrophage Migration Inhibitory Factor in complex with a biaryltr... -

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Basic information

Entry
Database: PDB / ID: 4wr8
TitleMacrophage Migration Inhibitory Factor in complex with a biaryltriazole inhibitor (3b-180)
ComponentsMacrophage migration inhibitory factor
KeywordsISOMERASE/ISOMERASE INHIBITOR / CD74 binding / tautomerase / inhibitor / complex / ISOMERASE-ISOMERASE 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 / phenylpyruvate tautomerase / L-dopachrome isomerase / dopachrome isomerase activity / phenylpyruvate tautomerase activity / positive regulation of lipopolysaccharide-mediated signaling pathway / cytokine receptor binding / positive regulation of arachidonic acid secretion / negative regulation of myeloid cell apoptotic process ...positive regulation of prostaglandin secretion involved in immune response / 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 lipopolysaccharide-mediated signaling pathway / cytokine receptor binding / positive regulation of arachidonic acid secretion / 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 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 / chemoattractant activity / positive regulation of protein kinase A signaling / protein homotrimerization / negative regulation of cellular senescence / negative regulation of DNA damage response, signal transduction by p53 class mediator / DNA damage response, signal transduction by p53 class mediator / 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 / positive regulation of cytokine production / cytokine activity / Cell surface interactions at the vascular wall / positive regulation of tumor necrosis factor production / positive regulation of peptidyl-tyrosine phosphorylation / cellular senescence / positive regulation of fibroblast proliferation / positive regulation of peptidyl-serine phosphorylation / secretory granule lumen / protease binding / vesicle / ficolin-1-rich granule lumen / positive regulation of ERK1 and ERK2 cascade / cell surface receptor signaling pathway / 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
4-[4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl]phenol / Macrophage migration inhibitory factor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.6 Å
AuthorsRobertson, M.J. / Baxter, R.H.G. / Jorgensen, W.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM32136 United States
CitationJournal: J.Am.Chem.Soc. / Year: 2015
Title: Design, synthesis, and protein crystallography of biaryltriazoles as potent tautomerase inhibitors of macrophage migration inhibitory factor.
Authors: Dziedzic, P. / Cisneros, J.A. / Robertson, M.J. / Hare, A.A. / Danford, N.E. / Baxter, R.H. / Jorgensen, W.L.
History
DepositionOct 23, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2015Group: Structure summary
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Derived calculations ...Author supporting evidence / Derived calculations / Other / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_audit_support ...entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 27, 2023Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Macrophage migration inhibitory factor
B: Macrophage migration inhibitory factor
C: Macrophage migration inhibitory factor
D: Macrophage migration inhibitory factor
E: Macrophage migration inhibitory factor
F: Macrophage migration inhibitory factor
G: Macrophage migration inhibitory factor
H: Macrophage migration inhibitory factor
I: Macrophage migration inhibitory factor
J: Macrophage migration inhibitory factor
K: Macrophage migration inhibitory factor
L: Macrophage migration inhibitory factor
M: Macrophage migration inhibitory factor
N: Macrophage migration inhibitory factor
O: Macrophage migration inhibitory factor
P: Macrophage migration inhibitory factor
Q: Macrophage migration inhibitory factor
R: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)229,28180
Polymers222,39118
Non-polymers6,89062
Water4,252236
1
A: Macrophage migration inhibitory factor
B: Macrophage migration inhibitory factor
C: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,21813
Polymers37,0653
Non-polymers1,15310
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Macrophage migration inhibitory factor
E: Macrophage migration inhibitory factor
F: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,24114
Polymers37,0653
Non-polymers1,17611
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
G: Macrophage migration inhibitory factor
H: Macrophage migration inhibitory factor
I: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,24114
Polymers37,0653
Non-polymers1,17611
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
J: Macrophage migration inhibitory factor
K: Macrophage migration inhibitory factor
L: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,24114
Polymers37,0653
Non-polymers1,17611
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
M: Macrophage migration inhibitory factor
N: Macrophage migration inhibitory factor
O: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,12212
Polymers37,0653
Non-polymers1,0579
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
P: Macrophage migration inhibitory factor
Q: Macrophage migration inhibitory factor
R: Macrophage migration inhibitory factor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,21813
Polymers37,0653
Non-polymers1,15310
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)138.644, 138.644, 266.586
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number90
Space group name H-MP4212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21D
31G
41J
51M
61P
12B
22E
32H
42K
52N
62Q
13C
23F
33I
43L
53O
63R

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A1 - 122
2114D1 - 122
3114G1 - 122
4114J1 - 122
5114M1 - 122
6114P1 - 122
1124B1 - 122
2124E1 - 122
3124H1 - 122
4124K1 - 122
5124N1 - 122
6124Q1 - 122
1134C1 - 122
2134F1 - 122
3134I1 - 122
4134L1 - 122
5134O1 - 122
6134R1 - 122

NCS ensembles :
ID
1
2
3

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.019716, 0.9998, -0.003396), (0.999805, 0.019719, 0.000872), (0.000939, -0.003378, -0.999994)71.04791, -69.43652, 156.92517
3given(-0.477313, 0.878717, 0.005336), (0.878729, 0.477282, 0.00619), (0.002892, 0.007643, -0.999967)102.34663, -61.17978, 67.1863
4given(0.557014, -0.830464, -0.008098), (-0.830482, -0.557042, 0.001618), (-0.005854, 0.005824, -0.999966)12.75042, -38.69252, 178.7968
5given(-0.841856, -0.5397, 0.001341), (0.539701, -0.841852, 0.00283), (-0.000398, 0.003106, 0.999995)31.81053, -58.60316, -21.52083
6given(-0.446671, -0.894692, 0.003241), (-0.894698, 0.446669, -0.001438), (-0.000161, -0.003542, -0.999994)7.1552, 30.99567, 89.74093
7given(1), (1), (1)
8given(-0.02436, 0.999701, -0.002039), (0.999703, 0.02436, 9.7E-5), (0.000147, -0.002036, -0.999998)71.18914, -69.23686, 156.98668
9given(-0.479078, 0.877771, 0.001536), (0.877771, 0.47908, -0.001152), (-0.001747, 0.000796, -0.999998)102.47787, -60.87022, 67.26852
10given(0.560322, -0.828167, -0.013359), (-0.828229, -0.560387, 0.001473), (-0.008706, 0.010239, -0.99991)13.54718, -38.78634, 179.00858
11given(-0.840312, -0.542096, 0.002833), (0.542094, -0.840255, 0.010329), (-0.003219, 0.010215, 0.999943)31.47441, -59.05301, -21.12565
12given(-0.456109, -0.889903, 0.006022), (-0.889914, 0.456062, -0.007817), (0.00421, -0.008925, -0.999951)7.4901, 31.70189, 89.37845
13given(1), (1), (1)
14given(-0.019645, 0.999807, -0.0007), (0.999806, 0.019644, -0.001321), (-0.001307, -0.000726, -0.999999)70.8399, -69.28894, 157.20357
15given(-0.473911, 0.880571, 0.001472), (0.880565, 0.473914, -0.003235), (-0.003546, -0.000237, -0.999994)102.2022, -61.23952, 67.32434
16given(0.556811, -0.83058, -0.009904), (-0.830612, -0.55685, 0.001509), (-0.006768, 0.007386, -0.99995)13.08136, -38.69421, 178.92838
17given(-0.841444, -0.540314, 0.005735), (0.540344, -0.841388, 0.009708), (-0.00042, 0.011268, 0.999936)31.39306, -58.99569, -21.19791
18given(-0.453897, -0.891027, 0.006984), (-0.891054, 0.453885, -0.003381), (-0.000157, -0.007758, -0.99997)7.45662, 31.52553, 89.50753

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Components

#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.: 18
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: Jurkat / Gene: MIF, GLIF, MMIF / Plasmid: pET11b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: P14174, phenylpyruvate tautomerase, L-dopachrome isomerase
#2: Chemical...
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 53 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-3TX / 4-[4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl]phenol


Mass: 288.303 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C17H12N4O
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 236 / Source method: isolated from a natural source / Formula: H2O

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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: 2.88 Å3/Da / Density % sol: 57.4 % / Description: thin plates
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 2.0M ammonium sulfate, 0.1M Tris-HCl pH 7, 3% isopropanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 22, 2013
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 80508 / % possible obs: 99.3 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.193 / Net I/σ(I): 7.8
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 4.2 % / Mean I/σ(I) obs: 1.65 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
HKL-2000data scaling
HKL-2000data reduction
RefinementResolution: 2.6→50 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.862 / SU B: 13.157 / SU ML: 0.274 / Cross valid method: THROUGHOUT / ESU R: 0.664 / ESU R Free: 0.34 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28048 4016 5 %RANDOM
Rwork0.2219 ---
obs0.22485 76047 99.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.847 Å2
Baniso -1Baniso -2Baniso -3
1-0.92 Å20 Å20 Å2
2--0.92 Å20 Å2
3----1.84 Å2
Refinement stepCycle: LAST / Resolution: 2.6→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15219 0 400 236 15855
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.01915975
X-RAY DIFFRACTIONr_bond_other_d0.0010.0214759
X-RAY DIFFRACTIONr_angle_refined_deg1.391.98621802
X-RAY DIFFRACTIONr_angle_other_deg0.763333847
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.76152034
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.70824.182581
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.941152344
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3571561
X-RAY DIFFRACTIONr_chiral_restr0.0710.22469
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.02118167
X-RAY DIFFRACTIONr_gen_planes_other0.0010.023624
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_it1.0072.3918190
X-RAY DIFFRACTIONr_mcbond_other1.0072.3918189
X-RAY DIFFRACTIONr_mcangle_it1.73.58410206
X-RAY DIFFRACTIONr_mcangle_other1.73.58410207
X-RAY DIFFRACTIONr_scbond_it1.1072.5217785
X-RAY DIFFRACTIONr_scbond_other1.1022.5187774
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.7593.74611579
X-RAY DIFFRACTIONr_long_range_B_refined4.1519.15417731
X-RAY DIFFRACTIONr_long_range_B_other4.13819.15917712
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION

Ens-IDDom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
11A1648medium positional0.290.5
11D1648medium positional0.270.5
11G1648medium positional0.310.5
11J1648medium positional0.280.5
11M1648medium positional0.290.5
11P1648medium positional0.230.5
22B1634medium positional0.310.5
22E1634medium positional0.310.5
22H1634medium positional0.290.5
22K1634medium positional0.260.5
22N1634medium positional0.310.5
22Q1634medium positional0.250.5
33C1697medium positional0.310.5
33F1697medium positional0.270.5
33I1697medium positional0.320.5
33L1697medium positional0.310.5
33O1697medium positional0.250.5
33R1697medium positional0.280.5
11A1648medium thermal2.562
11D1648medium thermal2.142
11G1648medium thermal3.052
11J1648medium thermal4.992
11M1648medium thermal4.732
11P1648medium thermal3.22
22B1634medium thermal2.32
22E1634medium thermal2.882
22H1634medium thermal2.962
22K1634medium thermal4.082
22N1634medium thermal4.852
22Q1634medium thermal2.882
33C1697medium thermal3.142
33F1697medium thermal3.762
33I1697medium thermal2.562
33L1697medium thermal3.42
33O1697medium thermal4.452
33R1697medium thermal2.812
LS refinement shellResolution: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.329 251 -
Rwork0.307 5605 -
obs--99.59 %

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