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- PDB-3coh: Crystal structure of Aurora-A in complex with a pentacyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 3coh
TitleCrystal structure of Aurora-A in complex with a pentacyclic inhibitor
ComponentsSerine/threonine-protein kinase 6Serine/threonine-specific protein kinase
KeywordsTRANSFERASE / Aurora-A / Inhibitor Complex / ATP-binding / Cell cycle / Kinase / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase
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 / spindle organization / positive regulation of mitochondrial fission / 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 / positive regulation of mitotic nuclear division / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / ciliary basal body / regulation of cytokinesis / negative regulation of protein binding / 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 / spindle microtubule / regulation of protein stability / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / spindle / kinetochore / mitotic spindle / 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 / basolateral plasma membrane / proteasome-mediated ubiquitin-dependent protein catabolic process / peptidyl-serine phosphorylation / Regulation of TP53 Activity through Phosphorylation / protein autophosphorylation / postsynaptic density / non-specific serine/threonine protein kinase / protein kinase activity / protein heterodimerization activity / cell division / protein phosphorylation / negative regulation of gene expression / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-83H / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsWiesmann, C. / Raswson, T.E. / Cochran, A.G.
CitationJournal: J.Med.Chem. / Year: 2008
Title: A pentacyclic aurora kinase inhibitor (AKI-001) with high in vivo potency and oral bioavailability.
Authors: Rawson, T.E. / Ruth, M. / Blackwood, E. / Burdick, D. / Corson, L. / Dotson, J. / Drummond, J. / Fields, C. / Georges, G.J. / Goller, B. / Halladay, J. / Hunsaker, T. / Kleinheinz, T. / ...Authors: Rawson, T.E. / Ruth, M. / Blackwood, E. / Burdick, D. / Corson, L. / Dotson, J. / Drummond, J. / Fields, C. / Georges, G.J. / Goller, B. / Halladay, J. / Hunsaker, T. / Kleinheinz, T. / Krell, H.W. / Li, J. / Liang, J. / Limberg, A. / McNutt, A. / Moffat, J. / Phillips, G. / Ran, Y. / Safina, B. / Ultsch, M. / Walker, L. / Wiesmann, C. / Zhang, B. / Zhou, A. / Zhu, B.Y. / Ruger, P. / Cochran, A.G.
History
DepositionMar 28, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase 6
B: Serine/threonine-protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,7124
Polymers62,0152
Non-polymers6972
Water0
1
A: Serine/threonine-protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,3562
Polymers31,0081
Non-polymers3481
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Serine/threonine-protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,3562
Polymers31,0081
Non-polymers3481
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.542, 99.542, 138.845
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number94
Space group name H-MP42212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: TRP / Beg label comp-ID: TRP / End auth comp-ID: SER / End label comp-ID: SER / Refine code: 1 / Auth seq-ID: 128 - 388 / Label seq-ID: 5 - 265

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Serine/threonine-protein kinase 6 / Serine/threonine-specific protein kinase / Aurora kinase A / Aurora-A / Serine/threonine kinase 15 / Aurora/IPL1-related kinase 1 / Aurora- ...Aurora kinase A / Aurora-A / Serine/threonine kinase 15 / Aurora/IPL1-related kinase 1 / Aurora-related kinase 1 / hARK1 / Breast tumor-amplified kinase


Mass: 31007.656 Da / Num. of mol.: 2 / Fragment: kinase domain (UNP residues 124-391) / Mutation: K124A, Q154N, A203S, R251K, T287A, T288A, E336D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AURKA, AIK, ARK1, AURA, BTAK, STK15, STK6 / Production host: Escherichia coli (E. coli)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-83H / 8-ethyl-3,10,10-trimethyl-4,5,6,8,10,12-hexahydropyrazolo[4',3':6,7]cyclohepta[1,2-b]pyrrolo[2,3-f]indol-9(1H)-one / 8-Ethyl-2,5,6,12-tetrahydro-3,10,10-trimethyl-9-oxo-pyrazolo[4'3':6,7]cyclohepta[1,2-b]pyrrolo[2,3-f]indole


Mass: 348.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24N4O

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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: 2.77 Å3/Da / Density % sol: 55.64 %
Crystal growTemperature: 291 K / Method: evaporation / pH: 7.5
Details: 30% PEG 3350, 0.2 M Ammonium sulfate, 0.1 M HEPES, pH 7.5, EVAPORATION, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.97945 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 6, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97945 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 19829 / Num. obs: 19773 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0
Reflection shellResolution: 2.7→2.8 Å / Rmerge(I) obs: 0.558 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
Blu-Icedata collection
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1MUO

1muo


Resolution: 2.7→20 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.908 / SU B: 31.124 / SU ML: 0.293 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.908 / ESU R Free: 0.361 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28044 1010 5.1 %RANDOM
Rwork0.24601 ---
all0.24937 19829 --
obs0.24769 18677 99.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 62.688 Å2
Baniso -1Baniso -2Baniso -3
1-2.44 Å20 Å20 Å2
2--2.44 Å20 Å2
3----4.87 Å2
Refinement stepCycle: LAST / Resolution: 2.7→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4048 0 52 0 4100
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0224204
X-RAY DIFFRACTIONr_bond_other_d0.0010.023866
X-RAY DIFFRACTIONr_angle_refined_deg1.4181.995694
X-RAY DIFFRACTIONr_angle_other_deg0.75938978
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4655490
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.96423.1200
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.40615748
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.3741534
X-RAY DIFFRACTIONr_chiral_restr0.0650.2610
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024570
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02882
X-RAY DIFFRACTIONr_nbd_refined0.2120.2776
X-RAY DIFFRACTIONr_nbd_other0.1670.23655
X-RAY DIFFRACTIONr_nbtor_refined0.1780.21985
X-RAY DIFFRACTIONr_nbtor_other0.0850.22536
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1180.263
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2850.219
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2790.262
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1870.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.4322.53188
X-RAY DIFFRACTIONr_mcbond_other0.4972.5996
X-RAY DIFFRACTIONr_mcangle_it3.0653974
X-RAY DIFFRACTIONr_scbond_it1.8822.52155
X-RAY DIFFRACTIONr_scangle_it2.83451720
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 3933 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
tight positional0.020.05
tight thermal0.050.5
LS refinement shellResolution: 2.7→2.755 Å / Total num. of bins used: 25
RfactorNum. reflection% reflection
Rfree0.44 58 -
Rwork0.327 1067 -
obs--99.56 %
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)
14.4513-0.7821-0.65321.98510.98073.88320.1245-0.64540.23860.57030.00920.1719-0.4766-0.4237-0.13370.14950.07440.0307-0.01720.0053-0.1-4.131372.866950.7678
21.69630.73150.57372.8443-0.3395.01980.3725-0.0438-0.30460.1659-0.1955-0.03890.33490.1253-0.177-0.1663-0.0653-0.0682-0.1882-0.0262-0.184517.462557.651554.1604
32.4305-0.2103-1.4454.77490.4715.7981-0.26020.318-0.29-0.67760.2389-0.17490.40070.54380.0213-0.0301-0.00720.02730.024-0.0401-0.086323.140947.586491.0956
42.54960.0816-0.0961.3611-0.80316.3887-0.0942-0.03850.08940.03830.44180.3753-0.8455-0.5389-0.34760.0361-0.02340.0566-0.19410.0678-0.06557.054968.426487.9777
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A128 - 217
2X-RAY DIFFRACTION2A218 - 388
3X-RAY DIFFRACTION3B128 - 217
4X-RAY DIFFRACTION4B218 - 388

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