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- PDB-8um5: X-ray structure of human SHIP1 Ptase-C2 domains covalently bound ... -

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Basic information

Entry
Database: PDB / ID: 8um5
TitleX-ray structure of human SHIP1 Ptase-C2 domains covalently bound to TREAT-AD (TAD) compound TAD-58547
ComponentsPhosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1
KeywordsLIPID BINDING PROTEIN / SHIP1 / INPP5D / alzheimer's disase / TREAT-AD / inhibitor
Function / homology
Function and homology information


inositol-polyphosphate 5-phosphatase / negative regulation of neutrophil differentiation / inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity / phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity / inositol-1,4,5-trisphosphate 5-phosphatase activity / inositol-polyphosphate 5-phosphatase activity / phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase / phosphoinositide 5-phosphatase / phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity / phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity ...inositol-polyphosphate 5-phosphatase / negative regulation of neutrophil differentiation / inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity / phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity / inositol-1,4,5-trisphosphate 5-phosphatase activity / inositol-polyphosphate 5-phosphatase activity / phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase / phosphoinositide 5-phosphatase / phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity / phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity / negative regulation of monocyte differentiation / phosphatidylinositol dephosphorylation / negative regulation of immune response / phosphatidylinositol biosynthetic process / phosphate-containing compound metabolic process / negative regulation of bone resorption / positive regulation of B cell differentiation / negative regulation of B cell proliferation / Synthesis of IP3 and IP4 in the cytosol / negative regulation of osteoclast differentiation / Synthesis of PIPs at the plasma membrane / PECAM1 interactions / negative regulation of interleukin-6 production / regulation of immune response / immunoglobulin mediated immune response / Interleukin receptor SHC signaling / negative regulation of signal transduction / positive regulation of erythrocyte differentiation / determination of adult lifespan / SH3 domain binding / Signaling by CSF1 (M-CSF) in myeloid cells / Downstream TCR signaling / T cell receptor signaling pathway / cytoskeleton / intracellular signal transduction / positive regulation of apoptotic process / membrane raft / apoptotic process / signal transduction / plasma membrane / cytosol
Similarity search - Function
Inositol polyphosphate-related phosphatase / Endonuclease/Exonuclease/phosphatase family 2 / Inositol polyphosphate phosphatase, catalytic domain homologues / Endonuclease/exonuclease/phosphatase superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily
Similarity search - Domain/homology
: / Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.86 Å
AuthorsMesecar, A.D. / Hamdani, A.K.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)1U54AG065181 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA023168 United States
CitationJournal: To Be Published
Title: X-ray structure of human SHIP1 Ptase-C2 domains covalently bound to TREAT-AD (TAD) compound TAD-58547
Authors: Hamdani, A.K. / Mesecar, A.D.
History
DepositionOct 17, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,3715
Polymers52,8781
Non-polymers4944
Water6,161342
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.643, 82.266, 59.749
Angle α, β, γ (deg.)90.000, 108.550, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1


Mass: 52877.574 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INPP5D / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92835
#2: Chemical ChemComp-X3F / 5-(1,4-oxazepan-4-yl)-6-propanoylpyridine-2-carbonitrile


Mass: 259.304 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H17N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 342 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.14 Å3/Da / Density % sol: 42.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 17-22% PEG 2000 MME, 7-10% PEG 3000 and 0.1M HEPES pH 7.0. Protein crystallization was performed in 24-well sitting drop plates with a 1:1 ratio of protein to reservoir solution (final ...Details: 17-22% PEG 2000 MME, 7-10% PEG 3000 and 0.1M HEPES pH 7.0. Protein crystallization was performed in 24-well sitting drop plates with a 1:1 ratio of protein to reservoir solution (final volume of 3 uL). Crystals were allowed to grow for at least 1 week at room temperature. Crystals at sizes appropriate for X-ray data collection were then cryoprotected with 2.5 uL of cryosolution (90% reservoir solution + 10% PEG 400.) Crystals were harvested with nylon loops and flash-frozen in liquid nitrogen.
Temp details: Room Temperature

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Oct 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.86→24.87 Å / Num. obs: 36968 / % possible obs: 98.35 % / Redundancy: 4.9 % / Biso Wilson estimate: 28.96 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.06535 / Rpim(I) all: 0.03248 / Rrim(I) all: 0.07319 / Net I/σ(I): 15.99
Reflection shellResolution: 1.861→1.927 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.6135 / Mean I/σ(I) obs: 2.49 / Num. unique obs: 16154 / CC1/2: 0.831 / CC star: 0.953 / Rpim(I) all: 0.3103 / Rrim(I) all: 0.6893 / % possible all: 90.79

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.86→24.87 Å / SU ML: 0.2121 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 20.4949
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2077 1843 5 %
Rwork0.1578 34991 -
obs0.1602 36834 98.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.77 Å2
Refinement stepCycle: LAST / Resolution: 1.86→24.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3643 0 31 343 4017
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00853902
X-RAY DIFFRACTIONf_angle_d0.97025303
X-RAY DIFFRACTIONf_chiral_restr0.0632576
X-RAY DIFFRACTIONf_plane_restr0.0075684
X-RAY DIFFRACTIONf_dihedral_angle_d6.5148515
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.86-1.910.28051250.22492386X-RAY DIFFRACTION88.45
1.91-1.970.24971410.19572685X-RAY DIFFRACTION98.36
1.97-2.030.26141430.18812698X-RAY DIFFRACTION98.61
2.03-2.10.24131420.17912696X-RAY DIFFRACTION98.95
2.1-2.190.22181410.17622677X-RAY DIFFRACTION98.98
2.19-2.290.24661420.17222707X-RAY DIFFRACTION99.3
2.29-2.410.19511440.16752725X-RAY DIFFRACTION99.48
2.41-2.560.24571440.17392742X-RAY DIFFRACTION99.79
2.56-2.760.21711430.18372725X-RAY DIFFRACTION99.72
2.76-3.030.22511450.16982735X-RAY DIFFRACTION99.83
3.03-3.470.22011430.15512729X-RAY DIFFRACTION99.97
3.47-4.370.17051440.13362717X-RAY DIFFRACTION98.45
4.37-24.870.18351460.13672769X-RAY DIFFRACTION99.12
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)
11.65307363475-0.03983167700420.09919255916391.455119713710.3257115753152.259732999970.0112503960196-0.383602154641-0.2445866188210.457200172701-0.1397111517810.5061922955750.426513690954-0.5994203278520.0574739300930.3070563298-0.09731860097330.1336150945890.4012918210550.01205612069010.37642295697-12.5511965571-20.505876087320.0482817667
21.74876444950.02901173828730.4469944871932.874412557051.527469203813.36328240306-0.09797491634940.03850725018620.0784576958991-0.15976140951-0.03450062257410.126532694617-0.218681611822-0.1847031239330.09944442241940.117278988154-0.003300807906680.01443878706120.1292094250270.02908556869650.150914952667-0.524019140881-10.82328529597.83984476727
31.920448163040.1186406705911.086534061222.150078817730.5093495525492.68446425543-0.166025286321-0.0696396477410.1849698290620.2041380718270.0309451651578-0.233099738502-0.1891823158920.1689594791460.09864593277660.1678632391960.0388372442345-0.01020878767510.1782971746890.02369390942580.1986116755349.76035661911-7.7475831041817.9106075948
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 395 through 504 )395 - 5041 - 110
22chain 'A' and (resid 505 through 617 )505 - 617111 - 223
33chain 'A' and (resid 618 through 856 )618 - 856224 - 451

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