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Entry
Database: PDB / ID: 7sqm
TitleDiscovery and Preclinical Pharmacology of INE963, A Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cure in Uncomplicated Malaria
ComponentsSerine/threonine-protein kinase haspin
KeywordsANTIVIRAL PROTEIN / imidazothiadiazole / antimalarial / single-dose cure / fast-acting / malaria
Function / homology
Function and homology information


histone H3T3 kinase activity / protein localization to chromosome, centromeric region / mitotic sister chromatid cohesion / mitotic spindle assembly checkpoint signaling / spindle / chromosome / mitotic cell cycle / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction ...histone H3T3 kinase activity / protein localization to chromosome, centromeric region / mitotic sister chromatid cohesion / mitotic spindle assembly checkpoint signaling / spindle / chromosome / mitotic cell cycle / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / centrosome / nucleoplasm / ATP binding / nucleus / cytoplasm
Similarity search - Function
Serine/threonine-protein kinase haspin, C-terminal / Domain of unknown function / Haspin like 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
Chem-A5G / Serine/threonine-protein kinase haspin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 Å
AuthorsShu, W. / Yokokawa, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: Malar. J. / Year: 2009
Title: Failure of artesunate-mefloquine combination therapy for uncompli-cated Plasmodium falciparum malaria in southern Cambodia.
Authors: Rogers, W.O. / Wongsrichanalai, C.
#1: Journal: Acta Crystallogr.,Sect.D / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D.
#2: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionNov 5, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 29, 2021Provider: 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

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase haspin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,9174
Polymers40,3831
Non-polymers5343
Water7,620423
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.026, 77.045, 86.308
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Serine/threonine-protein kinase haspin / Germ cell-specific gene 2 protein / H-haspin / Haploid germ cell-specific nuclear protein kinase


Mass: 40383.176 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HASPIN, GSG2
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q8TF76, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A5G / 1-[(4S)-5-(2,4-difluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-4-methylpiperidin-4-amine / INE963


Mass: 349.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H17F2N5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 423 / 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: 3.01 Å3/Da / Density % sol: 59.08 %
Crystal growTemperature: 294 K / Method: evaporation / Details: 0.1M NA CITRATE PH5, 20% PEG6K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 1.78→57.48 Å / Num. obs: 47421 / % possible obs: 100 % / Redundancy: 12.8 % / Biso Wilson estimate: 18.55 Å2 / CC1/2: 0.996 / CC star: 0.999 / Rmerge(I) obs: 0.22 / Rpim(I) all: 0.06783 / Net I/σ(I): 9.93
Reflection shellResolution: 1.78→1.844 Å / Redundancy: 12.9 % / Rmerge(I) obs: 1.975 / Mean I/σ(I) obs: 3.13 / Num. unique obs: 63 / CC1/2: 0.9 / CC star: 0.975 / Rpim(I) all: 0.5651 / % possible all: 99.79

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
PHENIX1.19.1_4122refinement
XDSdata reduction
Aimlessdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2VUW

2vuw


Resolution: 1.78→57.48 Å / SU ML: 0.1995 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.4888
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2046 2253 4.76 %
Rwork0.1734 45055 -
obs0.1749 47308 99.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.61 Å2
Refinement stepCycle: LAST / Resolution: 1.78→57.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2732 0 36 423 3191
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112847
X-RAY DIFFRACTIONf_angle_d1.18013855
X-RAY DIFFRACTIONf_chiral_restr0.0775426
X-RAY DIFFRACTIONf_plane_restr0.0094512
X-RAY DIFFRACTIONf_dihedral_angle_d6.3713402
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.78-1.820.29451440.26612754X-RAY DIFFRACTION99.69
1.82-1.860.27881270.25572801X-RAY DIFFRACTION99.86
1.86-1.910.28361210.23082771X-RAY DIFFRACTION99.59
1.91-1.960.23741540.2112772X-RAY DIFFRACTION99.86
1.96-2.020.23681290.19252780X-RAY DIFFRACTION99.76
2.02-2.080.23451290.18672822X-RAY DIFFRACTION100
2.08-2.160.20181350.17172776X-RAY DIFFRACTION100
2.16-2.240.22071520.16742772X-RAY DIFFRACTION99.93
2.24-2.340.19841450.17292803X-RAY DIFFRACTION99.97
2.34-2.470.19971380.17312821X-RAY DIFFRACTION99.97
2.47-2.620.23971450.17032805X-RAY DIFFRACTION99.97
2.62-2.830.23791340.17162817X-RAY DIFFRACTION100
2.83-3.110.18841450.16482841X-RAY DIFFRACTION99.97
3.11-3.560.16511440.15412832X-RAY DIFFRACTION99.97
3.56-4.480.17411570.13942869X-RAY DIFFRACTION99.93
4.48-57.480.19131540.17953019X-RAY DIFFRACTION99.91
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)
11.65403688001-0.674229151402-0.8858420672343.460860699-0.5120156233741.68655088286-0.0691601861980.000459377570294-0.129452909795-0.2742199774690.0672171833517-0.2621671394140.02603852876150.212763755790.1150823568560.177664299032-0.01935847901110.02125432706880.14006703506-0.02456498495310.13362095957539.211169734910.643387821-25.6556548516
22.329498762110.0508386653254-0.3863087533791.45428448129-0.3992457244161.59180305655-0.0442229555101-0.209745262330.08385309646070.0860295025094-0.0522896640908-0.0446836075671-0.3089691742170.1873915227520.0483106220130.149565614419-0.0739564385491-0.005775521292880.118948423484-0.0154255751920.074704731882632.963322474716.1598310952-16.0435773713
35.156936931693.29456929156-0.2523766003813.57992160425-0.8279434223271.24090791850.00424733370835-0.121269137513-0.158082291648-0.0564368438039-0.162365386322-0.2706318304610.01909048620510.06414024843160.0776068091260.1614004735780.02692853251520.004342249815560.1134769574530.01976619967990.10952593214335.26024111440.611258046693-15.1904916362
40.7091628006210.855699736419-0.6462829273741.89180962893-0.9765099434891.23114902024-0.122031432190.105064201272-0.0376158729015-0.1679211425930.0889880400095-0.07609424934730.04505255694590.01413982821050.01717076296640.1195738969660.01194476144380.002767223685830.114156618776-0.001959370332060.11389658503929.33889849873.53771572857-19.4524416861
51.9412326904-0.245618364254-0.6983573894932.281992572370.09290187048772.382139370520.109713345257-0.2741922959630.4268040122560.242826577235-0.06815280711150.0797828328748-0.3109562611590.111740185852-0.04139745484280.240958044528-0.07113777549920.04561717866780.13599815294-0.04877397060480.16285742256733.205649097726.1123090683-16.1159783447
64.253339480990.903844613985-2.2083199431.3289984714-0.8492183199042.276482566310.154626241213-0.005358107867580.1854819449580.203100602390.02443253990430.280473168757-0.266839902388-0.223890575925-0.09105145603470.1747947306790.03409588831510.04267001970560.1285149979990.01212667815180.1616598801520.410640639411.7389477927-11.7960392341
71.81006573371-0.341546786816-0.4669729939651.252253724440.02282966565751.413442254480.03806276862120.00933492726247-0.02138187128530.0467860468931-0.03590546470760.0895615005085-0.00643167557438-0.0942341216061-0.007153582461170.107012078033-0.006275906704230.02256773733610.0910570462066-0.002373182853620.075853047136221.5957157281-2.03619704711-7.66154079781
82.412505453090.19277420472-0.1997726021352.830161190750.2092890278562.805903929090.176096374162-0.6060986077670.5740712612530.611824320604-0.24846461956-0.081292080448-0.6491994870880.4095532214150.0525064873640.365181498115-0.110300878506-0.02764490517390.369424514662-0.06588480222420.24214410558436.35424921625.043080822184.81500897628
92.40790408625-0.134847502753-0.4863934636611.90231184645-0.008071581162161.526544827990.147149248434-0.1016780379750.3749237368070.0611973677873-0.04026122450960.222164520503-0.357405652044-0.270658931359-0.09523210228670.2261391009550.02620757298880.0886804317660.203179325602-0.01370559734760.15497293662715.30424766795.400812852173.66761803802
102.98515272164-0.567893991973-0.6068239625091.81725244257-0.2744166755311.6069554586-0.0227512480418-0.324727747246-0.0701940472030.1620786348750.06321880067870.27281317422-0.0510603239629-0.162955133101-0.04680253810380.208549851326-0.02918096213280.07432464330240.2081469088030.02288975745480.13617163464313.1993781075-5.043625763636.72137085009
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 453 through 487 )453 - 4871 - 35
22chain 'A' and (resid 488 through 528 )488 - 52836 - 76
33chain 'A' and (resid 529 through 547 )529 - 54777 - 95
44chain 'A' and (resid 548 through 570 )548 - 57096 - 118
55chain 'A' and (resid 571 through 598 )571 - 598119 - 146
66chain 'A' and (resid 599 through 621 )599 - 621147 - 169
77chain 'A' and (resid 622 through 701 )622 - 701170 - 249
88chain 'A' and (resid 702 through 737 )702 - 737250 - 285
99chain 'A' and (resid 738 through 764 )738 - 764286 - 312
1010chain 'A' and (resid 765 through 798 )765 - 798313 - 346

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