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- PDB-8tk2: HUMAN VH1-RELATED DUAL-SPECIFICITY PHOSPHATASE (VHR) complexed wi... -

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Basic information

Entry
Database: PDB / ID: 8tk2
TitleHUMAN VH1-RELATED DUAL-SPECIFICITY PHOSPHATASE (VHR) complexed with 2-((2,4-difluorobenzyl)amino)-2-oxoacetic acid
ComponentsDual specificity protein phosphatase 3
KeywordsHYDROLASE / PROTEIN DUAL-SPECIFICITY PHOSPHATASE / VHR
Function / homology
Function and homology information


receptor signaling protein tyrosine kinase inhibitor activity / MAP kinase phosphatase activity / protein tyrosine/serine/threonine phosphatase activity / negative regulation of chemotaxis / negative regulation of T cell activation / positive regulation of focal adhesion disassembly / ERKs are inactivated / dephosphorylation / negative regulation of JNK cascade / regulation of focal adhesion assembly ...receptor signaling protein tyrosine kinase inhibitor activity / MAP kinase phosphatase activity / protein tyrosine/serine/threonine phosphatase activity / negative regulation of chemotaxis / negative regulation of T cell activation / positive regulation of focal adhesion disassembly / ERKs are inactivated / dephosphorylation / negative regulation of JNK cascade / regulation of focal adhesion assembly / motile cilium / negative regulation of T cell receptor signaling pathway / protein-serine/threonine phosphatase / negative regulation of epidermal growth factor receptor signaling pathway / protein serine/threonine phosphatase activity / phosphatase activity / peptidyl-tyrosine dephosphorylation / immunological synapse / cytoskeletal protein binding / negative regulation of MAPK cascade / protein-tyrosine-phosphatase / positive regulation of mitotic cell cycle / protein tyrosine phosphatase activity / protein tyrosine kinase binding / cellular response to epidermal growth factor stimulus / negative regulation of cell migration / receptor tyrosine kinase binding / negative regulation of ERK1 and ERK2 cascade / cytoskeleton / protein kinase binding / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
Atypical dual specificity phosphatase, subfamily A / Dual specificity phosphatase, catalytic domain / Dual specificity phosphatase, catalytic domain / Dual specificity phosphatase, catalytic domain / Dual specificity protein phosphatase domain profile. / Dual specificity protein phosphatase 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
: / DI(HYDROXYETHYL)ETHER / Dual specificity protein phosphatase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsAleshin, A.E. / Wu, J. / Lambert, L.J. / Cosford, N.D.P. / Tautz, L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)1R21 AI160161 United States
CitationJournal: Acs Omega / Year: 2025
Title: Fragment Screening Identifies Novel Allosteric Binders and Binding Sites in the VHR ( DUSP3 ) Phosphatase.
Authors: Wu, J. / Baranowski, M.R. / Aleshin, A.E. / Isiorho, E.A. / Lambert, L.J. / De Backer, L.J.S. / Han, Y.N. / Das, R. / Sheffler, D.J. / Bobkov, A.A. / Lemberikman, A.M. / Keedy, D.A. / Cosford, N.D.P. / Tautz, L.
History
DepositionJul 25, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dual specificity protein phosphatase 3
B: Dual specificity protein phosphatase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,1816
Polymers40,5662
Non-polymers6154
Water4,324240
1
A: Dual specificity protein phosphatase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,4982
Polymers20,2831
Non-polymers2151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dual specificity protein phosphatase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,6824
Polymers20,2831
Non-polymers3993
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)35.536, 44.328, 59.863
Angle α, β, γ (deg.)78.07, 89.99, 81.69
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Dual specificity protein phosphatase 3 / Dual specificity protein phosphatase VHR / Vaccinia H1-related phosphatase / VHR


Mass: 20283.000 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DUSP3, VHR / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P51452, protein-serine/threonine phosphatase, protein-tyrosine-phosphatase
#2: Chemical ChemComp-I1Y / {[(2,4-difluorophenyl)methyl]amino}(oxo)acetic acid


Mass: 215.154 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C9H7F2NO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 240 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.25 Å3/Da / Density % sol: 45.32 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: Protein-compound mixture in 50 mM TRIS-Cl pH 8.5, 1 mM TCEP, 0.5 mM EDTA, 5% DMSO were mixed with the precipitant solution (100 mM Bis-Tris pH 6.5, 50 mM NH4F, 28% (w/v) PEGME-2000) and ...Details: Protein-compound mixture in 50 mM TRIS-Cl pH 8.5, 1 mM TCEP, 0.5 mM EDTA, 5% DMSO were mixed with the precipitant solution (100 mM Bis-Tris pH 6.5, 50 mM NH4F, 28% (w/v) PEGME-2000) and equilibrated against the precipitant solution.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 7, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.7→38.69 Å / Num. obs: 34755 / % possible obs: 89.4 % / Redundancy: 2 % / Rmerge(I) obs: 0.049 / Net I/σ(I): 8.8
Reflection shellResolution: 1.7→1.73 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.229 / Mean I/σ(I) obs: 2.7 / Num. unique obs: 1610 / % possible all: 80.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0411refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→38.69 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.951 / SU B: 2.764 / SU ML: 0.088 / Cross valid method: THROUGHOUT / ESU R: 0.127 / ESU R Free: 0.126 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22265 2065 5.9 %RANDOM
Rwork0.17587 ---
obs0.1786 32683 89.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 29.235 Å2
Baniso -1Baniso -2Baniso -3
1-0.75 Å2-1.78 Å20.41 Å2
2--1.04 Å2-0.55 Å2
3----2.4 Å2
Refinement stepCycle: 1 / Resolution: 1.7→38.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2804 0 41 240 3085
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0123029
X-RAY DIFFRACTIONr_bond_other_d0.0010.0162874
X-RAY DIFFRACTIONr_angle_refined_deg1.431.6474110
X-RAY DIFFRACTIONr_angle_other_deg0.4861.5766616
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8025389
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.042520
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.50710530
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0730.2448
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023716
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02720
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_it2.7712.871517
X-RAY DIFFRACTIONr_mcbond_other2.7612.8711517
X-RAY DIFFRACTIONr_mcangle_it3.9815.1481919
X-RAY DIFFRACTIONr_mcangle_other3.9815.1511920
X-RAY DIFFRACTIONr_scbond_it3.5223.3091512
X-RAY DIFFRACTIONr_scbond_other3.5213.3111513
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.3275.8982192
X-RAY DIFFRACTIONr_long_range_B_refined6.89132.83479
X-RAY DIFFRACTIONr_long_range_B_other6.85931.753413
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.743 Å
RfactorNum. reflection% reflection
Rfree0.257 140 -
Rwork0.238 2207 -
obs--83.26 %

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