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- PDB-6cmr: Closed structure of active SHP2 mutant E76D bound to SHP099 inhibitor -

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Basic information

Entry
Database: PDB / ID: 6cmr
TitleClosed structure of active SHP2 mutant E76D bound to SHP099 inhibitor
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE/HYDROLASE Inhibitor / protein tyrosine phosphatase / src homology domain 2 / inactive state / active mutant / HYDROLASE / HYDROLASE-HYDROLASE Inhibitor complex
Function / homology
Function and homology information


atrioventricular canal development / genitalia development / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / positive regulation of lipopolysaccharide-mediated signaling pathway / Interleukin-37 signaling / Signaling by Leptin / negative regulation of cell adhesion mediated by integrin ...atrioventricular canal development / genitalia development / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / positive regulation of lipopolysaccharide-mediated signaling pathway / Interleukin-37 signaling / Signaling by Leptin / negative regulation of cell adhesion mediated by integrin / positive regulation of ossification / MET activates PTPN11 / negative regulation of chondrocyte differentiation / face morphogenesis / Regulation of RUNX1 Expression and Activity / Signal regulatory protein family interactions / ERBB signaling pathway / Interleukin-20 family signaling / Interleukin-6 signaling / Co-inhibition by CTLA4 / PI-3K cascade:FGFR3 / STAT5 activation downstream of FLT3 ITD mutants / Platelet sensitization by LDL / negative regulation of T cell activation / PI-3K cascade:FGFR2 / peptide hormone receptor binding / PI-3K cascade:FGFR4 / MAPK3 (ERK1) activation / negative regulation of type I interferon production / PI-3K cascade:FGFR1 / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / inner ear development / Prolactin receptor signaling / PECAM1 interactions / peptidyl-tyrosine dephosphorylation / non-membrane spanning protein tyrosine phosphatase activity / fibroblast growth factor receptor signaling pathway / Regulation of IFNA/IFNB signaling / RET signaling / positive regulation of intracellular signal transduction / Interleukin-3, Interleukin-5 and GM-CSF signaling / Co-inhibition by PD-1 / PI3K Cascade / ephrin receptor signaling pathway / positive regulation of insulin receptor signaling pathway / regulation of protein-containing complex assembly / Regulation of IFNG signaling / GAB1 signalosome / negative regulation of T cell receptor signaling pathway / negative regulation of T cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / GPVI-mediated activation cascade / T cell costimulation / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / phosphotyrosine residue binding / FRS-mediated FGFR4 signaling / phosphoprotein phosphatase activity / FRS-mediated FGFR1 signaling / protein-tyrosine-phosphatase / Tie2 Signaling / FLT3 Signaling / protein tyrosine phosphatase activity / cell adhesion molecule binding / positive regulation of interferon-beta production / Downstream signal transduction / cellular response to epidermal growth factor stimulus / protein tyrosine kinase binding / positive regulation of D-glucose import across plasma membrane / insulin receptor binding / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Negative regulation of FGFR3 signaling / cellular response to mechanical stimulus / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / brain development / Signaling by SCF-KIT / Spry regulation of FGF signaling / receptor tyrosine kinase binding / vasodilation / epidermal growth factor receptor signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / cytokine-mediated signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / Interferon alpha/beta signaling / positive regulation of tumor necrosis factor production / PIP3 activates AKT signaling / heart development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / signaling receptor complex adaptor activity / molecular adaptor activity / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cadherin binding / focal adhesion / protein kinase binding
Similarity search - Function
Protein-tyrosine phosphatase, non-receptor type-6, -11 / SH2 domain / SHC Adaptor Protein / Protein tyrosine phosphatase superfamily / Protein-Tyrosine Phosphatase; Chain A / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Protein-tyrosine phosphatase / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase, catalytic ...Protein-tyrosine phosphatase, non-receptor type-6, -11 / SH2 domain / SHC Adaptor Protein / Protein tyrosine phosphatase superfamily / Protein-Tyrosine Phosphatase; Chain A / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Protein-tyrosine phosphatase / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase, catalytic / Protein tyrosine phosphatase, catalytic domain motif / 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 / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Alpha-Beta Complex / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-5OD / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.21 Å
AuthorsPadua, R.A.P. / Sun, Y. / Marko, I. / Pitsawong, W. / Kern, D.
Funding support Brazil, United States, 3items
OrganizationGrant numberCountry
Brazilian National Council for Scientific and Technological Development (CNPq)233809/2014-7 Brazil
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM100966 United States
CitationJournal: Nat Commun / Year: 2018
Title: Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2.
Authors: Padua, R.A.P. / Sun, Y. / Marko, I. / Pitsawong, W. / Stiller, J.B. / Otten, R. / Kern, D.
History
DepositionMar 6, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Apr 17, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,3432
Polymers60,9911
Non-polymers3521
Water1,42379
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.270, 54.360, 221.530
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Space group name HallP22ab(z,x,y)
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y+1/2,-z+1/2
#4: -x,-y+1/2,z+1/2

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Components

#1: Protein Tyrosine-protein phosphatase non-receptor type 11 / Protein-tyrosine phosphatase 1D / PTP-1D / Protein-tyrosine phosphatase 2C / PTP-2C / SH-PTP2 / Shp2 / SH-PTP3


Mass: 60990.789 Da / Num. of mol.: 1 / Mutation: E76D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN11, PTP2C, SHPTP2 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q06124, protein-tyrosine-phosphatase
#2: Chemical ChemComp-5OD / 6-(4-azanyl-4-methyl-piperidin-1-yl)-3-[2,3-bis(chloranyl)phenyl]pyrazin-2-amine / SHP099


Mass: 352.262 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H19Cl2N5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.17 Å3/Da / Density % sol: 43.19 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 15% PEG 20,000 and 10 mM potassium hydrogen tartrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 0.99997 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 14, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 2.21→52.79 Å / Num. obs: 25969 / % possible obs: 99.92 % / Redundancy: 6.1 % / Biso Wilson estimate: 44.34 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.1645 / Rpim(I) all: 0.07346 / Net I/σ(I): 5.85
Reflection shellResolution: 2.21→2.289 Å / Redundancy: 6.6 % / Num. unique obs: 2566 / Rpim(I) all: 0.7128 / % possible all: 100

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Processing

Software
NameVersionClassification
Blu-Icedata collection
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
Cootmodel building
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DGP

4dgp


Resolution: 2.21→52.79 Å / SU ML: 0.3859 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 29.2629 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.2605 3722 7.73 %
Rwork0.2242 44446 -
obs0.2271 25954 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 58.13 Å2
Refinement stepCycle: LAST / Resolution: 2.21→52.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3850 0 23 79 3952
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00163951
X-RAY DIFFRACTIONf_angle_d0.45695353
X-RAY DIFFRACTIONf_chiral_restr0.0405590
X-RAY DIFFRACTIONf_plane_restr0.0019693
X-RAY DIFFRACTIONf_dihedral_angle_d9.91632339
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
2.21-2.240.37361360.36351617256699.49
2.24-2.270.36771430.3586171699.68
2.27-2.30.35681390.356163299.77
2.3-2.330.42041400.35411602100
2.33-2.370.35881400.317165999.94
2.37-2.40.30981320.3097166699.89
2.4-2.440.33511340.3052165399.94
2.44-2.480.35161390.30551608100
2.48-2.530.31931410.30391676100
2.53-2.580.31981400.29321672100
2.58-2.630.38051340.30571630100
2.63-2.690.40211340.30711615100
2.69-2.750.35471420.2929171499.95
2.75-2.820.29191330.26441596100
2.82-2.90.25571370.25821662100
2.9-2.980.38881360.25871657100
2.98-3.080.29431390.2705162399.94
3.08-3.190.29261410.2525166899.83
3.19-3.310.27351390.24481619100
3.31-3.470.24131380.2191166799.83
3.47-3.650.2711390.20261645100
3.65-3.880.23211380.1885164699.44
3.88-4.180.21671370.1721164499.44
4.18-4.60.17561380.1539164199.89
4.6-5.260.16411380.1419164699.61
5.26-6.630.20011350.1881162099.55
6.63-52.810.24081400.2082165299.78
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.814010217450.6708632519494.373673330892.692007997480.6141923477667.744240550860.193191385058-0.2660272063260.2628989489660.0408143023013-0.2727341843390.5317301724990.202837364721-1.052144209330.08481613456210.346570633265-0.08769157566760.005731450198830.653689243727-0.02509409136760.536653206512-14.5874460859-5.3183906117121.2114212855
26.42262467564-0.8015521917253.976249214165.51356998482.045952923973.681811185290.4985260882880.661618079448-0.8691413677330.351526117918-0.08205987581620.1542952086941.009426365220.0050477885806-0.444893006340.491700300335-0.0612075747509-0.0003492357635640.607848903551-0.02437209664970.587887408841-7.20430090077-13.812003795719.9971598741
30.8026153727231.001083187460.3315521865821.416636209630.4978345401654.84138960896-0.1699443917860.04333435996750.145423264687-0.416830124405-0.0245084384657-0.00526398262428-0.607047029463-0.2624029656140.2101948009720.8119412923770.122756371464-0.007857598850860.4654676648770.05964536232190.609976693797-1.3966001465917.840841779910.0230896401
42.50168426919-1.169294840071.155059891972.39782792805-0.7055143088412.72225749547-0.00484493633388-0.19769335402-0.02748820595770.1684037612430.09677482329350.1526265149210.0918107903069-0.242754479957-0.0825670439270.408175967444-0.08480280577820.04308005107220.424674718430.05221231153010.3954315564289.14468795272-0.85389886987540.9344603288
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 66 )
2X-RAY DIFFRACTION2chain 'A' and (resid 67 through 103 )
3X-RAY DIFFRACTION3chain 'A' and (resid 104 through 245 )
4X-RAY DIFFRACTION4chain 'A' and (resid 246 through 528 )

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