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- PDB-6c83: Structure of Aurora A (122-403) bound to inhibitory Monobody Mb2 ... -

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Basic information

Entry
Database: PDB / ID: 6c83
TitleStructure of Aurora A (122-403) bound to inhibitory Monobody Mb2 and AMPPCP
Components
  • Aurora kinase A
  • Mb2 Monobody
Keywordstransferase/inhibitor / Transferase / Aurora A / Monobody / AMPPCP / Kinase / Activation / Allostery / Cell cycle / Cancer / transferase-inhibitor complex
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Aurora kinase A / Aurora kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Immunoglobulins / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsHoemberger, M. / Kutter, S. / Zorba, A. / Nguyen, V. / Shohei, A. / Shohei, K. / Kern, D.
Funding support United States, 3items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM100966 United States
Department of Energy (DOE, United States)DE-FG02-05ER15699 United States
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2019
Title: Allosteric modulation of a human protein kinase with monobodies.
Authors: Zorba, A. / Nguyen, V. / Koide, A. / Hoemberger, M. / Zheng, Y. / Kutter, S. / Kim, C. / Koide, S. / Kern, D.
History
DepositionJan 24, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jul 10, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID
Revision 1.3Jul 24, 2019Group: Data collection / Database references / Structure summary
Category: audit_author / citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.4Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Mar 16, 2022Group: Author supporting evidence / Database references / Category: database_2 / pdbx_audit_support
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization
Revision 1.6Oct 4, 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

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Assembly

Deposited unit
A: Aurora kinase A
B: Aurora kinase A
C: Mb2 Monobody
D: Mb2 Monobody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,7006
Polymers85,6894
Non-polymers1,0102
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: AUC (sedimentation velocity runs) were performed at 50k rpm, 18C and showed persistent dimer of 2x Aurora*Mb2 even at low concentrations of Aurora.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6060 Å2
ΔGint-32 kcal/mol
Surface area28310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.047, 69.916, 173.718
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 Aurora kinase A / / Aurora 2 / Aurora/IPL1-related kinase 1 / hARK1 / Breast tumor-amplified kinase / Serine/threonine- ...Aurora 2 / Aurora/IPL1-related kinase 1 / hARK1 / Breast tumor-amplified kinase / Serine/threonine-protein kinase 15 / Serine/threonine-protein kinase 6 / Serine/threonine-protein kinase aurora-A


Mass: 32990.754 Da / Num. of mol.: 2
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) / Strain (production host): BL21(DE3)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Protein Mb2 Monobody


Mass: 9853.987 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
#3: Chemical ChemComp-ACP / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / ADENOSINE-5'-[BETA, GAMMA-METHYLENE]TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Comment: AMP-PCP, energy-carrying molecule analogue*YM

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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: 2.23 Å3/Da / Density % sol: 44.94 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Crystals of dephosphorylated Aurora A (122-403) in complex with Monobody Mb2 and AMPPCP were obtained by mixing a 1:1 ratio of 0.24mM Aurora A, 0.25mM Mb2 and 2.5mM AMPPCP in 20mM TrisHCl pH ...Details: Crystals of dephosphorylated Aurora A (122-403) in complex with Monobody Mb2 and AMPPCP were obtained by mixing a 1:1 ratio of 0.24mM Aurora A, 0.25mM Mb2 and 2.5mM AMPPCP in 20mM TrisHCl pH 7.5, 200mM NaCl,20mM MgCl2, 10% glycerol, 5mM TCEP with mother liquor (0.1M Bis-Tris pH 5.5, 0.2M NaCl, 25% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 28, 2017
RadiationMonochromator: Si(111) side scattering I-beam bent single crystal
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.55→64.86 Å / Num. obs: 25451 / % possible obs: 98.47 % / Redundancy: 5.3 % / Biso Wilson estimate: 62.83 Å2 / Rmerge(I) obs: 0.053 / Net I/σ(I): 13.1
Reflection shellResolution: 2.55→2.62 Å

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Processing

Software
NameVersionClassification
PHENIX1.13rc2_2986refinement
xia20.4.0.0data reduction
Aimless0.5.21data scaling
PHASER2.8.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4c3r, 3k2m

4c3r

3k2m


Resolution: 2.55→46.82 Å / SU ML: 0.4642 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 37.2497
RfactorNum. reflection% reflection
Rfree0.3221 2000 7.86 %
Rwork0.2637 --
obs0.2683 25450 98.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 73.75 Å2
Refinement stepCycle: LAST / Resolution: 2.55→46.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4875 0 62 0 4937
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00155060
X-RAY DIFFRACTIONf_angle_d0.40676896
X-RAY DIFFRACTIONf_chiral_restr0.0398765
X-RAY DIFFRACTIONf_plane_restr0.003869
X-RAY DIFFRACTIONf_dihedral_angle_d2.67542911
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.55-2.610.40021410.36131660X-RAY DIFFRACTION98.42
2.61-2.680.39321400.35991636X-RAY DIFFRACTION99.33
2.68-2.760.43131410.35441656X-RAY DIFFRACTION98.63
2.76-2.850.4671410.35441653X-RAY DIFFRACTION98.46
2.85-2.950.38781390.35431629X-RAY DIFFRACTION98
2.95-3.070.43511410.35561650X-RAY DIFFRACTION98.95
3.07-3.210.4521410.32911655X-RAY DIFFRACTION97.93
3.21-3.380.40651400.3231645X-RAY DIFFRACTION98.29
3.38-3.590.3211430.29251667X-RAY DIFFRACTION98
3.59-3.870.32151430.25281673X-RAY DIFFRACTION98.37
3.87-4.260.29811430.22341683X-RAY DIFFRACTION98.17
4.26-4.870.26211450.21131695X-RAY DIFFRACTION98.92
4.87-6.140.28811470.24941727X-RAY DIFFRACTION99
6.14-46.830.28051550.22661821X-RAY DIFFRACTION98.46

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