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- PDB-5zan: Crystal Structure of Aurora-A in complex with a new Quinazoline i... -

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Basic information

Entry
Database: PDB / ID: 5zan
TitleCrystal Structure of Aurora-A in complex with a new Quinazoline inhibitor
ComponentsAurora kinase A
KeywordsTRANSFERASE/INHIBITOR / Drug Design / TRANSFERASE / 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 / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of mitotic nuclear division / mitotic spindle organization / ciliary basal body / negative regulation of protein binding / regulation of signal transduction by p53 class mediator / regulation of cytokinesis / 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 / spindle / mitotic 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 / centrosome / protein serine/threonine kinase activity / 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-9A6 / Aurora kinase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsCheng, B. / Lu, G. / Zhou, H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China81773636 China
CitationJournal: To Be Published
Title: Optimization of Novel Quinazolines as Potent and Orally Bioavailable Aurora Kinase Inhibitors
Authors: Long, L. / Peng, W. / Pan, Y. / Cheng, B. / Tu, Z. / Long, Z. / Zhou, H. / Liu, Q. / Lu, G.
History
DepositionFeb 7, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 13, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_low

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aurora kinase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9862
Polymers32,5601
Non-polymers4261
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12560 Å2
Unit cell
Length a, b, c (Å)84.740, 84.740, 171.484
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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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: 32560.346 Da / Num. of mol.: 1 / Fragment: Catalytic domain, UNP residues 123-403
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 (E. coli)
References: UniProt: O14965, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-9A6 / 7-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(E)-2-phenylethenyl]quinazolin-4-amine


Mass: 425.529 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N7 / Feature type: SUBJECT OF INVESTIGATION

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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: 2.81 Å3/Da / Density % sol: 56.3 %
Crystal growTemperature: 293 K / Method: evaporation
Details: 0.22M Sodium citrate tribasic dihydrate pH 6.0, 10%(v/v) 2-Propanol, 22(w/v) Polyethylene glycol 4,000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.85→50 Å / Num. obs: 9017 / % possible obs: 98.8 % / Redundancy: 11.2 % / Rmerge(I) obs: 0.066 / Net I/σ(I): 54.4
Reflection shellResolution: 2.85→2.9 Å / Rmerge(I) obs: 0.561 / Mean I/σ(I) obs: 5.8 / Num. unique obs: 428

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Processing

Software
NameVersionClassification
REFMAC5.8.0103refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4UTD

4utd
PDB Unreleased entry


Resolution: 2.85→50 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.909 / SU B: 44.874 / SU ML: 0.388 / Cross valid method: THROUGHOUT / ESU R: 1.494 / ESU R Free: 0.397 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28128 428 4.8 %RANDOM
Rwork0.25512 ---
obs0.25644 8528 98.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 100.013 Å2
Baniso -1Baniso -2Baniso -3
1--1.34 Å2-0.67 Å2-0 Å2
2---1.34 Å2-0 Å2
3---4.34 Å2
Refinement stepCycle: 1 / Resolution: 2.85→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1976 0 32 0 2008
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192062
X-RAY DIFFRACTIONr_bond_other_d0.0060.021871
X-RAY DIFFRACTIONr_angle_refined_deg1.3171.9782814
X-RAY DIFFRACTIONr_angle_other_deg1.02534260
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3225256
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.2122.92189
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.6215295
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7341514
X-RAY DIFFRACTIONr_chiral_restr0.0680.2311
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212360
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02501
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.9547.251030
X-RAY DIFFRACTIONr_mcbond_other3.9537.2491029
X-RAY DIFFRACTIONr_mcangle_it5.77210.8621284
X-RAY DIFFRACTIONr_mcangle_other5.7710.8641285
X-RAY DIFFRACTIONr_scbond_it4.7417.2481032
X-RAY DIFFRACTIONr_scbond_other4.7397.251033
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.44110.8081531
X-RAY DIFFRACTIONr_long_range_B_refined7.65359.0782367
X-RAY DIFFRACTIONr_long_range_B_other7.65459.0942368
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.849→2.923 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 27 -
Rwork0.331 610 -
obs--98.61 %
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)
10.6578-0.5111-0.32790.42110.48484.50170.0819-0.1955-0.34320.04920.35460.18980.6336-0.0584-0.43640.1417-0.1650.00350.547-0.11230.4266-0.814222.442-9.7774
23.5937-4.97062.67187.0858-3.08065.66350.25440.2446-0.2262-0.3434-0.0540.16060.23910.3553-0.20040.1205-0.11940.0290.584-0.10650.4841-5.136724.4296-15.6101
32.514-2.3958-1.43732.45522.14844.58680.01660.03470.3434-0.01870.0537-0.2909-0.0332-0.0302-0.07030.1574-0.1282-0.00090.42350.13820.1992-13.413339.0259-7.2942
41.3152-0.37270.15552.21371.93273.3783-0.090.7953-0.02210.5181-0.26980.26410.1454-0.30540.35970.1844-0.03210.0850.5545-0.05390.349-24.147231.4947-6.1279
50.3222-1.0049-0.51636.00861.35051.2815-0.04450.3074-0.02280.3824-0.33510.6626-0.1043-0.52220.37960.1155-0.0416-0.04250.49780.08390.532-28.969541.2321-2.0198
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A127 - 185
2X-RAY DIFFRACTION2A186 - 210
3X-RAY DIFFRACTION3A211 - 269
4X-RAY DIFFRACTION4A270 - 324
5X-RAY DIFFRACTION5A325 - 389

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