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- PDB-8afr: Pim1 in complex with 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic ... -

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Basic information

Entry
Database: PDB / ID: 8afr
TitlePim1 in complex with 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid and Pimtide
Components
  • Pimtide
  • Serine/threonine-protein kinase pim-1
KeywordsTRANSFERASE / SERINE KINASE / KINASE / COMPLEX / PIM1 / PIM / PIM-1 / INHIBITOR / TUMORIGENISIS / CANCER / PIMTIDE / PROTO ONCOGEN / ATP / PHOSPHORYLATION / APOPTOSIS / CELL CYCLE
Function / homology
Function and homology information


positive regulation of cardioblast proliferation / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / cellular detoxification / STAT5 activation downstream of FLT3 ITD mutants / transcription factor binding / ribosomal small subunit binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of cardiac muscle cell proliferation / negative regulation of innate immune response ...positive regulation of cardioblast proliferation / regulation of hematopoietic stem cell proliferation / vitamin D receptor signaling pathway / cellular detoxification / STAT5 activation downstream of FLT3 ITD mutants / transcription factor binding / ribosomal small subunit binding / positive regulation of cyclin-dependent protein serine/threonine kinase activity / positive regulation of cardiac muscle cell proliferation / negative regulation of innate immune response / positive regulation of brown fat cell differentiation / Signaling by FLT3 fusion proteins / positive regulation of TORC1 signaling / protein serine/threonine kinase activator activity / regulation of transmembrane transporter activity / positive regulation of protein serine/threonine kinase activity / negative regulation of DNA-binding transcription factor activity / cellular response to type II interferon / manganese ion binding / Interleukin-4 and Interleukin-13 signaling / protein autophosphorylation / non-specific serine/threonine protein kinase / protein stabilization / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / negative regulation of apoptotic process / nucleolus / apoptotic process / positive regulation of DNA-templated transcription / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Serine/threonine-protein kinase pim-1/2/3 / : / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid / Serine/threonine-protein kinase pim-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsHochban, P.M.M. / Heine, A. / Diederich, W.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Pose, duplicate, then elaborate: Steps towards increased affinity for inhibitors targeting the specificity surface of the Pim-1 kinase.
Authors: Heyder, L. / Hochban, P.M.M. / Taylor, C. / Chevillard, F. / Siefker, C. / Iking, C. / Borchardt, H. / Aigner, A. / Klebe, G. / Heine, A. / Kolb, P. / Diederich, W.E.
History
DepositionJul 18, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: 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

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase pim-1
C: Pimtide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,2173
Polymers36,9492
Non-polymers2681
Water2,000111
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)96.437, 96.437, 80.250
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65
Space group name HallP65
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: -x,-y,z+1/2

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Components

#1: Protein Serine/threonine-protein kinase pim-1


Mass: 35356.141 Da / Num. of mol.: 1 / Mutation: R250G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIM1 / Plasmid: pLIC-SGC / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P11309, non-specific serine/threonine protein kinase
#2: Protein/peptide Pimtide


Mass: 1592.850 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Synthetic construct (others)
#3: Chemical ChemComp-M0F / 4-((6-hydroxybenzofuran-3-yl)methyl)benzoic acid


Mass: 268.264 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 111 / 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: 3 Å3/Da / Density % sol: 59.4 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 100 mM bis-tris-propane (pH7.0), 10 % ethylene glycol, 0.3% DMSO, 20% PEG3350, 200 mM LiCl
PH range: 6.8 - 7.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 7, 2019 / Details: Sagitally bended Si111-crystal
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.15→48.22 Å / Num. obs: 22836 / % possible obs: 98.1 % / Redundancy: 13.9 % / Biso Wilson estimate: 40.22 Å2 / CC1/2: 1 / Rsym value: 0.055 / Net I/σ(I): 32.97
Reflection shellResolution: 2.15→2.28 Å / Redundancy: 13.9 % / Mean I/σ(I) obs: 5.12 / Num. unique obs: 3583 / CC1/2: 0.963 / % possible all: 95.7

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
MxCuBEdata collection
XDS1.02data reduction
XDS1.02data scaling
Coot0.7.1model building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5NDT

5ndt


Resolution: 2.15→48.22 Å / SU ML: 0.1586 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.9775 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.1909 1142 5.01 %
Rwork0.1642 21671 -
obs0.1655 22813 98.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.77 Å2
Refinement stepCycle: LAST / Resolution: 2.15→48.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2159 0 20 111 2290
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00412266
X-RAY DIFFRACTIONf_angle_d0.62583079
X-RAY DIFFRACTIONf_chiral_restr0.0462331
X-RAY DIFFRACTIONf_plane_restr0.0049415
X-RAY DIFFRACTIONf_dihedral_angle_d20.03881344
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.250.2391380.19392614X-RAY DIFFRACTION94.8
2.25-2.360.22171420.17322692X-RAY DIFFRACTION98.16
2.36-2.510.23651420.17632699X-RAY DIFFRACTION98.71
2.51-2.710.22661430.17862715X-RAY DIFFRACTION99
2.71-2.980.18271420.17212707X-RAY DIFFRACTION97.54
2.98-3.410.23431440.1752729X-RAY DIFFRACTION99.38
3.41-4.290.17061440.15282728X-RAY DIFFRACTION98.56
4.29-48.220.16471470.15562787X-RAY DIFFRACTION99.02
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)
11.12398953359-0.1598230889920.1061643994021.231925404370.4941091118092.3594213250.0437419428461-0.0207630008229-0.04000323675690.1538709933810.03341425540880.01435121030450.00421048211495-0.1384668935553.74675930375E-60.25626403221-0.0196795732167-0.01375007390050.3295286630240.01510273209070.28787215031598.1102689414210.7660140221.97293208167
20.4287149447390.216139799706-0.3039673375170.125817498651-0.1602865576870.2477535959110.451856641596-0.291116558768-0.2968657486490.575089816214-0.161778898304-0.1004573920670.4302699161890.06165148126390.01992326380780.6464448654040.110302592955-0.129610653640.5348701043450.03868886059610.446013093121104.835391483202.07843226213.6390147187
30.3644042825940.286835668023-0.03553113639320.7005828281390.3099036624531.352567178440.3633140635990.255293950556-0.0674220076724-0.227314160136-0.33456978777-0.1512459958740.613890092640.7261653433520.0420665421850.3535419968780.0769132010039-0.03446047230540.6639112098320.03154937969760.547004818683124.126008513198.475095505-4.71558316109
40.2515242561340.05041257751130.1378689237560.172122425021-0.008060680132050.1097277722780.1190736837180.5606258589460.116886811172-0.4935989310930.08163364335050.097406611744-0.07825240947330.2797419422220.01175459084610.3753571189850.05952885654770.001862320769710.465178054389-0.1304701529010.476041180975109.287031426199.459220568-11.7050762271
50.78533068353-0.526667121602-0.3727814282830.61537655246-0.241773903171.086866276120.110420477327-0.2704707137070.04089498441480.01788439864230.124811883005-0.3466211612940.03868355513570.7237469267140.07705237051470.3324081831460.0403270473265-0.05960959844590.526001066742-0.03757326760010.409171408368115.82968742204.59677038-0.155700843015
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 141 through 305 )
2X-RAY DIFFRACTION2chain 'C' and (resid 2 through 10 )
3X-RAY DIFFRACTION3chain 'A' and (resid 33 through 73 )
4X-RAY DIFFRACTION4chain 'A' and (resid 74 through 105 )
5X-RAY DIFFRACTION5chain 'A' and (resid 106 through 140 )

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