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- PDB-5iu2: Discovery of imidazoquinolines as a novel class of potent, select... -

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Basic information

Entry
Database: PDB / ID: 5iu2
TitleDiscovery of imidazoquinolines as a novel class of potent, selective and in vivo efficacious COT kinase inhibitors
ComponentsMitogen-activated protein kinase kinase kinase 8
KeywordsTRANSFERASE / COT / Tpl-2 / MAP3K8 / kinase / inhibitor / complex
Function / homology
Function and homology information


mitogen-activated protein kinase kinase kinase / CD28 dependent PI3K/Akt signaling / MAP kinase kinase kinase activity / T cell costimulation / MAP3K8 (TPL2)-dependent MAPK1/3 activation / cell cycle / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / magnesium ion binding ...mitogen-activated protein kinase kinase kinase / CD28 dependent PI3K/Akt signaling / MAP kinase kinase kinase activity / T cell costimulation / MAP3K8 (TPL2)-dependent MAPK1/3 activation / cell cycle / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / magnesium ion binding / ATP binding / cytosol
Similarity search - Function
Mitogen-activated protein (MAP) kinase kinase kinase 8 / 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 domain profile. ...Mitogen-activated protein (MAP) kinase kinase kinase 8 / 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 domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-6DA / Mitogen-activated protein kinase kinase kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsGutmann, S. / Hinniger, A.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors.
Authors: Glatthar, R. / Stojanovic, A. / Troxler, T. / Mattes, H. / Mobitz, H. / Beerli, R. / Blanz, J. / Gassmann, E. / Druckes, P. / Fendrich, G. / Gutmann, S. / Martiny-Baron, G. / Spence, F. / ...Authors: Glatthar, R. / Stojanovic, A. / Troxler, T. / Mattes, H. / Mobitz, H. / Beerli, R. / Blanz, J. / Gassmann, E. / Druckes, P. / Fendrich, G. / Gutmann, S. / Martiny-Baron, G. / Spence, F. / Hornfeld, J. / Peel, J.E. / Sparrer, H.
History
DepositionMar 17, 2016Deposition site: RCSB / Processing site: PDBE
SupersessionAug 24, 2016ID: 4Y83, 4Y85
Revision 1.0Aug 24, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2016Group: Database references
Revision 1.2Feb 7, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase kinase kinase 8
B: Mitogen-activated protein kinase kinase kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,2864
Polymers75,2702
Non-polymers1,0152
Water2,702150
1
A: Mitogen-activated protein kinase kinase kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1432
Polymers37,6351
Non-polymers5081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase kinase kinase 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1432
Polymers37,6351
Non-polymers5081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.480, 87.430, 125.120
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein Mitogen-activated protein kinase kinase kinase 8 / Cancer Osaka thyroid oncogene / Proto-oncogene c-Cot / Serine/threonine-protein kinase cot / Tumor ...Cancer Osaka thyroid oncogene / Proto-oncogene c-Cot / Serine/threonine-protein kinase cot / Tumor progression locus 2 / TPL-2


Mass: 37635.199 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
References: UniProt: P41279, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-6DA / N-[2-(morpholin-4-yl)ethyl]-6-(8-phenyl-1H-imidazo[4,5-c][1,7]naphthyridin-1-yl)-1,3-benzothiazol-2-amine


Mass: 507.609 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H25N7OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 150 / Source method: isolated from a natural source / Formula: H2O

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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: 2.38 Å3/Da / Density % sol: 48.3 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Bis-Tris pH 7, 1.7 m ammonium sulfate, 0.01 M proline. Protein solution (COT:compound 1:1) was mixed with an equal volume (1 uL) of reservoir solution. Equilibration was done over 500 ...Details: 0.1 M Bis-Tris pH 7, 1.7 m ammonium sulfate, 0.01 M proline. Protein solution (COT:compound 1:1) was mixed with an equal volume (1 uL) of reservoir solution. Equilibration was done over 500 uL reservoir solution.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 21, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→71.66 Å / Num. obs: 20386 / % possible obs: 99.9 % / Redundancy: 6.53 % / Biso Wilson estimate: 50.76 Å2 / Rsym value: 0.129 / Net I/σ(I): 12.53
Reflection shellResolution: 2.7→2.81 Å / Rsym value: 0.492

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Y85

4y85


Resolution: 2.7→58.01 Å / Cor.coef. Fo:Fc: 0.8904 / Cor.coef. Fo:Fc free: 0.851 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.344 / SU Rfree Cruickshank DPI: 0.344
RfactorNum. reflection% reflectionSelection details
Rfree0.2579 1019 5 %RANDOM
Rwork0.2326 ---
obs0.2339 20361 99.81 %-
Displacement parametersBiso mean: 29.06 Å2
Baniso -1Baniso -2Baniso -3
1--4.06 Å20 Å20 Å2
2--1.2262 Å20 Å2
3---2.8338 Å2
Refine analyzeLuzzati coordinate error obs: 0.429 Å
Refinement stepCycle: 1 / Resolution: 2.7→58.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4775 0 74 150 4999
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084980HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.986784HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1625SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes92HARMONIC2
X-RAY DIFFRACTIONt_gen_planes728HARMONIC5
X-RAY DIFFRACTIONt_it4980HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.37
X-RAY DIFFRACTIONt_other_torsion17.99
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion655SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5642SEMIHARMONIC4
LS refinement shellResolution: 2.7→2.85 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.3598 147 5.01 %
Rwork0.2965 2789 -
all0.2998 2936 -
obs--99.81 %
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)
10.4391-0.16720.02581.42790.39180.32660.0293-0.06120.0302-0.1315-0.0004-0.1273-0.0601-0.0454-0.0289-0.1306-0.01440.0275-0.0750.0734-0.0317-14.422517.2603-6.6568
20.20320.0091-0.04280.19240.45320.998-0.00510.10910.043-0.0593-0.05960.0313-0.0963-0.07580.0647-0.17160.0241-0.0018-0.03090.0022-0.0602-43.4190.6358-18.5099
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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