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- PDB-7umv: Structure of MAP kinase phosphatase 5 in complex with 3,3-dimethy... -

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Basic information

Entry
Database: PDB / ID: 7umv
TitleStructure of MAP kinase phosphatase 5 in complex with 3,3-dimethyl-1-((5,6-dihydropyrido[2,3-h]quinazolin-2-yl)thio)butan-2-one, an allosteric inhibitor
ComponentsDual specificity protein phosphatase 10
KeywordsHYDROLASE/INHIBITOR / phosphatase / protein-tyrosine phosphatase / dual specificity phosphatase / phosphatase-inhibitor complex / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of epithelium regeneration / MAP kinase phosphatase activity / protein tyrosine/threonine phosphatase activity / MAP kinase tyrosine phosphatase activity / MAP kinase tyrosine/serine/threonine phosphatase activity / regulation of adaptive immune response / regulation of brown fat cell differentiation / negative regulation of epithelial cell migration / negative regulation of p38MAPK cascade / negative regulation of oligodendrocyte differentiation ...negative regulation of epithelium regeneration / MAP kinase phosphatase activity / protein tyrosine/threonine phosphatase activity / MAP kinase tyrosine phosphatase activity / MAP kinase tyrosine/serine/threonine phosphatase activity / regulation of adaptive immune response / regulation of brown fat cell differentiation / negative regulation of epithelial cell migration / negative regulation of p38MAPK cascade / negative regulation of oligodendrocyte differentiation / Signaling by MAPK mutants / RAF-independent MAPK1/3 activation / JUN kinase binding / dephosphorylation / negative regulation of stress-activated MAPK cascade / negative regulation of JNK cascade / positive regulation of regulatory T cell differentiation / mitogen-activated protein kinase p38 binding / protein-serine/threonine phosphatase / protein serine/threonine phosphatase activity / phosphatase activity / oligodendrocyte differentiation / negative regulation of respiratory burst involved in inflammatory response / stress-activated MAPK cascade / protein-tyrosine-phosphatase / negative regulation of cell migration / negative regulation of ERK1 and ERK2 cascade / negative regulation of epithelial cell proliferation / Negative regulation of MAPK pathway / response to lipopolysaccharide / signal transduction / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase phosphatase / Dual specificity phosphatase, catalytic domain / Dual specificity phosphatase, catalytic domain / Dual specificity phosphatase, catalytic domain / Rhodanese Homology Domain / Dual specificity protein phosphatase domain profile. / Dual specificity protein phosphatase domain / Rhodanese-like domain / Rhodanese domain profile. / Rhodanese-like domain superfamily ...Mitogen-activated protein (MAP) kinase phosphatase / Dual specificity phosphatase, catalytic domain / Dual specificity phosphatase, catalytic domain / Dual specificity phosphatase, catalytic domain / Rhodanese Homology Domain / Dual specificity protein phosphatase domain profile. / Dual specificity protein phosphatase domain / Rhodanese-like domain / Rhodanese domain profile. / Rhodanese-like domain superfamily / Rhodanese-like domain / Tyrosine specific protein phosphatases active site. / Protein-tyrosine phosphatase, active site / Tyrosine specific protein phosphatases domain profile. / Tyrosine-specific protein phosphatases domain / Protein-tyrosine phosphatase-like
Similarity search - Domain/homology
ACETATE ION / Chem-NUU / Dual specificity protein phosphatase 10
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsGannam, Z.T.K. / Jamali, H. / Lolis, E. / Anderson, K.S. / Ellman, J.A. / Bennett, A.M.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)AR66003 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM122473 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI055403 United States
National Institutes of Health/National Institute on Minority Health and Health Disparities (NIH/NIMHD)MD122473 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Defining the structure-activity relationship for a novel class of allosteric MKP5 inhibitors.
Authors: Gannam, Z.T.K. / Jamali, H. / Kweon, O.S. / Herrington, J. / Shillingford, S.R. / Papini, C. / Gentzel, E. / Lolis, E. / Bennett, A.M. / Ellman, J.A. / Anderson, K.S.
History
DepositionApr 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 5, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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

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Assembly

Deposited unit
A: Dual specificity protein phosphatase 10
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,8223
Polymers17,4501
Non-polymers3722
Water2,594144
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area160 Å2
ΔGint-1 kcal/mol
Surface area7460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.962, 76.962, 89.238
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number172
Space group name H-MP64
Space group name HallP64
Symmetry operation#1: x,y,z
#2: x-y,x,z+2/3
#3: y,-x+y,z+1/3
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z

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Components

#1: Protein Dual specificity protein phosphatase 10 / Mitogen-activated protein kinase phosphatase 5 / MKP-5


Mass: 17449.961 Da / Num. of mol.: 1 / Fragment: UNP residues 320-467
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DUSP10, MKP5 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9Y6W6, protein-serine/threonine phosphatase, protein-tyrosine-phosphatase
#2: Chemical ChemComp-NUU / 1-{[(10aP)-5,6-dihydropyrido[2,3-h]quinazolin-2-yl]sulfanyl}-3,3-dimethylbutan-2-one


Mass: 313.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H19N3OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 144 / Source method: isolated from a natural source / Formula: H2O
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: 4.37 Å3/Da / Density % sol: 71.87 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100 mM Tris, pH 7.5, 200 mM ammonium acetate, 40% w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 11, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.797→53.4 Å / Num. obs: 27956 / % possible obs: 99.78 % / Redundancy: 17.7 % / Biso Wilson estimate: 29.38 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.09617 / Rrim(I) all: 0.09881 / Net I/σ(I): 19.97
Reflection shellResolution: 1.797→1.861 Å / Redundancy: 8.7 % / Rmerge(I) obs: 1.102 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 23832 / CC1/2: 0.89 / Rrim(I) all: 1.168 / % possible all: 98.4

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
PHASERphasing
Cootmodel building
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6MC1

6mc1


Resolution: 1.8→53.4 Å / SU ML: 0.2242 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 18.6362
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.172 1990 7.13 %
Rwork0.1543 25905 -
obs0.1555 27895 99.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.66 Å2
Refinement stepCycle: LAST / Resolution: 1.8→53.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1212 0 26 144 1382
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01851282
X-RAY DIFFRACTIONf_angle_d1.41751740
X-RAY DIFFRACTIONf_chiral_restr0.0988187
X-RAY DIFFRACTIONf_plane_restr0.0115227
X-RAY DIFFRACTIONf_dihedral_angle_d20.5471478
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.840.39671400.35511805X-RAY DIFFRACTION98.13
1.84-1.890.28031410.27611841X-RAY DIFFRACTION99.35
1.89-1.950.26211450.24241824X-RAY DIFFRACTION99.8
1.95-2.010.2241410.1621845X-RAY DIFFRACTION99.9
2.01-2.080.20271450.16451871X-RAY DIFFRACTION99.95
2.08-2.170.18841390.16921832X-RAY DIFFRACTION100
2.17-2.260.1931450.17511860X-RAY DIFFRACTION100
2.26-2.380.15351410.1451837X-RAY DIFFRACTION100
2.38-2.530.17091430.14241851X-RAY DIFFRACTION100
2.53-2.730.16781400.15221861X-RAY DIFFRACTION100
2.73-30.18411360.16891860X-RAY DIFFRACTION100
3-3.440.16851410.15961864X-RAY DIFFRACTION100
3.44-4.330.15091460.12681869X-RAY DIFFRACTION100
4.33-53.40.13871470.1321885X-RAY DIFFRACTION99.9

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