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- PDB-8ssp: AurA bound to danusertib and activating monobody Mb1 -

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Basic information

Entry
Database: PDB / ID: 8ssp
TitleAurA bound to danusertib and activating monobody Mb1
Components
  • Aurora kinase A
  • Mb1
KeywordsTRANSFERASE / Complex / Kinase / Monobody
Function / homology
Function and homology information


Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / axon hillock / spindle assembly involved in female meiosis I / cilium disassembly / spindle pole centrosome / positive regulation of oocyte maturation / histone H3S10 kinase activity / chromosome passenger complex / pronucleus ...Interaction between PHLDA1 and AURKA / regulation of centrosome cycle / axon hillock / spindle assembly involved in female meiosis I / cilium disassembly / spindle pole centrosome / positive regulation of oocyte maturation / histone H3S10 kinase activity / chromosome passenger complex / pronucleus / meiotic spindle / mitotic centrosome separation / germinal vesicle / protein localization to centrosome / anterior/posterior axis specification / centrosome localization / neuron projection extension / positive regulation of mitochondrial fission / spindle organization / mitotic spindle pole / SUMOylation of DNA replication proteins / spindle midzone / regulation of G2/M transition of mitotic cell cycle / centriole / protein serine/threonine/tyrosine kinase activity / positive regulation of mitotic cell cycle / AURKA Activation by TPX2 / mitotic spindle organization / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of mitotic nuclear division / ciliary basal body / negative regulation of protein binding / regulation of cytokinesis / regulation of signal transduction by p53 class mediator / molecular function activator activity / liver regeneration / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / regulation of protein stability / mitotic spindle / spindle / kinetochore / response to wounding / microtubule cytoskeleton / G2/M transition of mitotic cell cycle / Regulation of PLK1 Activity at G2/M Transition / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / mitotic cell cycle / midbody / proteasome-mediated ubiquitin-dependent protein catabolic process / basolateral plasma membrane / peptidyl-serine phosphorylation / Regulation of TP53 Activity through Phosphorylation / microtubule / postsynaptic density / protein autophosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / protein heterodimerization activity / cell division / negative regulation of gene expression / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / glutamatergic synapse / apoptotic process / ubiquitin protein ligase binding / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / nucleoplasm / ATP binding / nucleus / cytosol
Similarity search - Function
Aurora kinase A / Aurora kinase / 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
Chem-627 / 1,3-PROPANDIOL / PHOSPHATE ION / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsLudewig, H. / Kim, C. / Kern, D.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2023
Title: A biophysical framework for double-drugging kinases.
Authors: Kim, C. / Ludewig, H. / Hadzipasic, A. / Kutter, S. / Nguyen, V. / Kern, D.
History
DepositionMay 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 6, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aurora kinase A
B: Mb1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,82513
Polymers43,4812
Non-polymers1,34311
Water2,018112
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4680 Å2
ΔGint-21 kcal/mol
Surface area16840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.517, 90.805, 143.130
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-668-

HOH

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Aurora kinase A / / Aurora 2 / Aurora/IPL1-related kinase 1 / ARK-1 / Aurora-related kinase 1 / Breast tumor-amplified ...Aurora 2 / Aurora/IPL1-related kinase 1 / ARK-1 / Aurora-related kinase 1 / Breast tumor-amplified kinase / Ipl1- and aurora-related kinase 1 / Serine/threonine-protein kinase 15 / Serine/threonine-protein kinase 6 / Serine/threonine-protein kinase Ayk1 / Serine/threonine-protein kinase aurora-A


Mass: 32903.676 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Gene: AURKA, AIK, AIRK1, ARK1, AURA, AYK1, BTAK, IAK1, STK15, STK6
Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Protein Mb1


Mass: 10577.592 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria)

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Non-polymers , 7 types, 123 molecules

#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#6: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#7: Chemical ChemComp-PDO / 1,3-PROPANDIOL / 1,3-Propanediol


Mass: 76.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O2
#8: Chemical ChemComp-627 / N-[(3E)-5-[(2R)-2-METHOXY-2-PHENYLACETYL]PYRROLO[3,4-C]PYRAZOL-3(5H)-YLIDENE]-4-(4-METHYLPIPERAZIN-1-YL)BENZAMIDE / Danusertib / PHA-739358


Mass: 474.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N6O3 / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 112 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.82 Å3/Da / Density % sol: 56.41 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Crystals of AurA in complex with Mb1 and danusertib were obtained by combining 2 uL of 300 uM (10 mg/mL) AurA + 315 uM (4 mg/mL) Mb1 + 2 mM AMPPCP + 4 mM MgCl2 with 2 ul reservoir of 0.1 M ...Details: Crystals of AurA in complex with Mb1 and danusertib were obtained by combining 2 uL of 300 uM (10 mg/mL) AurA + 315 uM (4 mg/mL) Mb1 + 2 mM AMPPCP + 4 mM MgCl2 with 2 ul reservoir of 0.1 M MES pH 6.5 + 0.2 M Ammonium sulfate + 4% (v/v) 1,3-propanediol + 15-18% PEG 8000. Streak seeding was used to obtain bigger crystals. Crystals were grown at 18 degC by hanging drop

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→45.4 Å / Num. obs: 15516 / % possible obs: 99.75 % / Redundancy: 7.1 % / Biso Wilson estimate: 39.56 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.1933 / Net I/σ(I): 8.74
Reflection shellResolution: 2.6→2.693 Å / Rmerge(I) obs: 1.341 / Mean I/σ(I) obs: 1.97 / Num. unique obs: 1519 / CC1/2: 0.871

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→45.4 Å / SU ML: 0.3581 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 28.4422
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2566 1065 6.89 %
Rwork0.1977 14403 -
obs0.2018 15468 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 51.63 Å2
Refinement stepCycle: LAST / Resolution: 2.6→45.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2868 0 87 112 3067
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00163045
X-RAY DIFFRACTIONf_angle_d0.44854128
X-RAY DIFFRACTIONf_chiral_restr0.0408437
X-RAY DIFFRACTIONf_plane_restr0.0037518
X-RAY DIFFRACTIONf_dihedral_angle_d6.9086434
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.720.36351400.30041749X-RAY DIFFRACTION99.06
2.72-2.860.36221220.27851762X-RAY DIFFRACTION99.31
2.86-3.040.32691340.25421787X-RAY DIFFRACTION99.64
3.04-3.280.32661250.23851777X-RAY DIFFRACTION99.69
3.28-3.610.24991390.20521797X-RAY DIFFRACTION99.85
3.61-4.130.25121400.16241788X-RAY DIFFRACTION99.9
4.13-5.20.16421310.14551826X-RAY DIFFRACTION100
5.2-45.40.24081340.18261917X-RAY DIFFRACTION99.61
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)
15.327784653840.39905772269-2.033582848912.7968168542-0.5099304683612.506364629590.0407960080574-0.2271528393690.02596413704520.8628275396020.01274905419620.160021158345-0.630442159704-0.197705599638-0.05366547384320.7410656568710.09613135731590.02693309071870.2584524568230.05785090235410.361093021302-24.9605392073-10.2664742546-21.0195604165
21.51852403962-0.57428898838-0.6980984242643.993599601660.3525702211452.71476482655-0.0118775365306-0.1307410772750.07652613789280.6799996373770.07489176766720.137933016974-0.290457898572-0.0339175086105-0.04428841425170.4540099561730.018742557305-0.02911867105290.2232425774190.008647220287260.302624168035-16.6101907038-22.8730640968-25.4185128057
34.240192637311.42297515886-1.034159863626.118989983-4.727493104236.82201709269-0.2060625881580.13136327936-0.2709377230740.439636216180.3944798000110.08982435471640.49388551393-0.266880450392-0.0602465966260.3692940261770.02709619875040.06194620212180.140610777688-0.03238440958950.190228659546-15.6667785179-27.2930661203-27.6820725102
41.19836431771-0.8971687843830.7357695692270.621398754449-0.3916893098110.575713586170.00291574772009-0.187842839412-0.1217194875620.8656976944970.2257756367220.1472980487370.191717106487-0.285572766606-0.254410581630.845917980672-0.112337703740.0616325751760.3413683280080.0397310596370.348806205113-20.7100039472-37.9887411103-21.8767490356
53.651228778160.950203043159-0.7539985790575.10126363605-0.6054696083922.36438693163-0.1217098951810.138812949154-0.2887898548620.01553215979570.0284045301611-0.08575097406830.707943027393-0.2520966804490.1476382366850.49822625977-0.04753420335370.01432863282490.205224967651-0.01972997962460.238529316468-16.2280795167-42.5140391312-36.105756242
64.50457183059-1.42215695475-0.5908041206221.75083882642-1.97045839895.52482949467-0.1111339530080.414995257789-0.4641418288210.587386161732-0.183897280583-1.061895345780.5947740118970.6258851738110.5339871103360.440364749230.0612068000683-0.08234162212760.1651817705760.111121237370.487017435826-0.237764329573-34.732395731-33.8275548836
75.380528402840.7676393784122.528702177125.10476076671.814373085972.56552483646-0.115723877802-0.4783495139-0.6019418440631.31721780711-0.425599373879-0.3706965001860.3008843787320.9425690288570.6277374781580.9321120871230.0274006778895-0.1267589142360.6902631376450.2550288614390.536728208887-15.9983298849-40.20210496974.65946783895
83.79719121715-3.641387234764.964701130274.69391658056-6.715550710132.331618264510.0344315586777-0.960899203919-0.1680513673551.44061392590.2694301087850.740110434433-0.772759784532-1.33757110942-0.6969782924881.255705140830.1098706501580.05245434406950.6296207827550.07177816396230.506854481005-21.5778241387-26.4167310866-0.931052461405
91.97269977366-0.3083164078271.016995251321.270921693021.464256469342.69562069088-0.530954584885-0.4429806130410.845281549-0.7842290464190.320100562494-0.133492648157-1.776659508261.46305874830.2422312590592.26165496689-0.572895973198-0.4002964091851.36265685682-0.2037748863780.441142718246-10.1330672502-28.232811769818.2981896684
103.03823342843-0.95217378283-0.4195080419952.43888697507-1.867563067222.2715686810.0151281082081-0.339937638377-0.2040856391840.4578292314790.02223203004480.227116570453-1.491810179320.1445978068890.1066970453431.30249941122-0.0615407131829-0.1406194914430.558175811590.02873595324750.358313370604-15.584616206-30.61846628264.88850987396
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 126 through 172 )AA126 - 1721 - 47
22chain 'A' and (resid 173 through 250 )AA173 - 25048 - 125
33chain 'A' and (resid 251 through 269 )AA251 - 269126 - 144
44chain 'A' and (resid 270 through 307 )AA270 - 307145 - 182
55chain 'A' and (resid 308 through 373 )AA308 - 373183 - 248
66chain 'A' and (resid 374 through 389 )AA374 - 389249 - 264
77chain 'B' and (resid 9 through 23 )BK9 - 231 - 15
88chain 'B' and (resid 24 through 44 )BK24 - 4416 - 36
99chain 'B' and (resid 45 through 51 )BK45 - 5137 - 43
1010chain 'B' and (resid 52 through 96 )BK52 - 9644 - 88

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