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- PDB-4d2w: Structure of MELK in complex with inhibitors -

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Basic information

Entry
Database: PDB / ID: 4d2w
TitleStructure of MELK in complex with inhibitors
ComponentsMATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
KeywordsTRANSFERASE / FRAGMENT BASED DRUG DESIGN
Function / homology
Function and homology information


neural precursor cell proliferation / intrinsic apoptotic signaling pathway in response to oxidative stress / hemopoiesis / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / G2/M transition of mitotic cell cycle / protein autophosphorylation / cell cortex / cell population proliferation / non-specific serine/threonine protein kinase ...neural precursor cell proliferation / intrinsic apoptotic signaling pathway in response to oxidative stress / hemopoiesis / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / G2/M transition of mitotic cell cycle / protein autophosphorylation / cell cortex / cell population proliferation / non-specific serine/threonine protein kinase / positive regulation of apoptotic process / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / calcium ion binding / lipid binding / ATP binding / membrane / plasma membrane
Similarity search - Function
Maternal embryonic leucine zipper kinase, catalytic domain / : / Maternal embryonic leucine zipper kinase, UBA domain / Kinase associated domain 1 (KA1) / Kinase associated domain 1 / Kinase associated domain 1 (KA1) profile. / KA1 domain/Ssp2, C-terminal / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site ...Maternal embryonic leucine zipper kinase, catalytic domain / : / Maternal embryonic leucine zipper kinase, UBA domain / Kinase associated domain 1 (KA1) / Kinase associated domain 1 / Kinase associated domain 1 (KA1) profile. / KA1 domain/Ssp2, C-terminal / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-NF5 / Maternal embryonic leucine zipper kinase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 1.92 Å
AuthorsJohnson, C.N. / Berdini, V. / Beke, L. / Bonnet, P. / Brehmer, D. / Coyle, J.E. / Day, P.J. / Frederickson, M. / Freyne, E.J.E. / Gilissen, R.A.H.J. ...Johnson, C.N. / Berdini, V. / Beke, L. / Bonnet, P. / Brehmer, D. / Coyle, J.E. / Day, P.J. / Frederickson, M. / Freyne, E.J.E. / Gilissen, R.A.H.J. / Hamlett, C.C.F. / Howard, S. / Meerpoel, L. / McMenamin, R. / Patel, S. / Rees, D.C. / Sharff, A. / Sommen, F. / Wu, T. / Linders, J.T.M.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase
Authors: Johnson, C.N. / Berdini, V. / Beke, L. / Bonnet, P. / Brehmer, D. / Coyle, J.E. / Day, P.J. / Frederickson, M. / Freyne, E.J.E. / Gilissen, R.A.H.J. / Hamlett, C.C.F. / Howard, S. / ...Authors: Johnson, C.N. / Berdini, V. / Beke, L. / Bonnet, P. / Brehmer, D. / Coyle, J.E. / Day, P.J. / Frederickson, M. / Freyne, E.J.E. / Gilissen, R.A.H.J. / Hamlett, C.C.F. / Howard, S. / Meerpoel, L. / Mcmenamin, R. / Patel, S. / Rees, D.C. / Sharff, A. / Sommen, F. / Wu, T. / Linders, J.T.M.
History
DepositionMay 13, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 8, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 28, 2015Group: Database references
Revision 1.2Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
B: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
C: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
D: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)164,8868
Polymers163,5054
Non-polymers1,3814
Water19,4021077
1
A: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
D: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,4434
Polymers81,7532
Non-polymers6902
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2510 Å2
ΔGint-10.8 kcal/mol
Surface area28390 Å2
MethodPISA
2
B: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
C: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,4434
Polymers81,7532
Non-polymers6902
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2770 Å2
ΔGint-10.7 kcal/mol
Surface area28250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.956, 74.947, 78.216
Angle α, β, γ (deg.)85.74, 70.07, 89.94
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE / HMELK / PROTEIN KINASE EG3 / PEG3 KINASE / PROTEIN KINASE PK38 / HPK38 / TYROSINE-PROTEIN KINASE MELK / MELK


Mass: 40876.273 Da / Num. of mol.: 4 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Description: IMAGE CLONE / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q14680, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-NF5 / 4-bromo-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)benzamide


Mass: 345.234 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H17BrN2O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1077 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsHIS TAG ADDED AND C-TERMINAL RESIDUES NOT INCLUDED (304)

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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: 2.26 Å3/Da / Density % sol: 46 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418
DetectorType: RIGAKU SATURN / Detector: CCD / Date: Sep 24, 2009 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.92→35.01 Å / Num. obs: 107563 / % possible obs: 94.5 % / Observed criterion σ(I): 0.75 / Redundancy: 1.9 % / Biso Wilson estimate: 35.2 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 4.9

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.92→35.01 Å / Cor.coef. Fo:Fc: 0.9404 / Cor.coef. Fo:Fc free: 0.9112 / SU R Cruickshank DPI: 0.178 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.182 / SU Rfree Blow DPI: 0.162 / SU Rfree Cruickshank DPI: 0.162
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL HAVE CCP4 ATOM TYPE FROM LIBRARY ATOMS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2468 5074 5 %RANDOM
Rwork0.2008 ---
obs0.2031 101580 94.76 %-
Displacement parametersBiso mean: 44.817 Å2
Baniso -1Baniso -2Baniso -3
1-5.559 Å21.7634 Å2-1.7244 Å2
2---2.8762 Å2-0.6897 Å2
3----2.6827 Å2
Refine analyzeLuzzati coordinate error obs: 0.275 Å
Refinement stepCycle: LAST / Resolution: 1.92→35.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10332 0 84 1077 11493
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.01210697HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.114467HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3796SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes254HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1559HARMONIC16
X-RAY DIFFRACTIONt_it10697HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.16
X-RAY DIFFRACTIONt_other_torsion18.94
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1346SEMIHARMONIC5
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_contact12811SEMIHARMONIC4
LS refinement shellResolution: 1.92→1.97 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2685 285 4.85 %
Rwork0.2326 5589 -
all0.2344 5874 -
obs--94.76 %
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)
11.5438-0.6188-0.0540.51271.00682.85110.040.15640.1848-0.1324-0.1028-0.1218-0.19760.18490.06280.00280.08720.0414-0.03320.0483-0.05388.7217-0.5381-12.4053
23.3563-0.725-0.8151.93290.15781.3673-0.0727-0.20110.15930.20160.07660.053-0.0586-0.0971-0.00390.01530.10920.0435-0.0807-0.0073-0.1555-11.16563.94366.024
32.8762-3.0136-0.89243.90290.50974.4553-0.1173-0.0902-0.15860.3126-0.0729-0.2230.44380.63510.1901-0.06390.1506-0.035-0.00630.0401-0.055119.6749-11.3264-0.5881
43.1360.6769-0.79491.8628-0.66711.7732-0.28040.35730.0264-0.30270.2305-0.10030.07020.00040.05-0.1064-0.0280.0267-0.0118-0.0186-0.0328-3.0186-34.3839-20.8843
52.3192-0.16-0.57971.2855-0.09232.0084-0.0773-0.0670.12070.09310.06460.09380.03060.06080.0126-0.06280.07260.0199-0.0995-0.0041-0.0257-23.2575-35.1813-2.6147
62.6876-0.81130.90570.7961.76811.9041-0.0242-0.3062-0.47240.19410.0201-0.3110.15580.35950.0042-0.2130.0417-0.03920.07370.08990.091410.6684-38.5104-7.7266
72.89321.1688-0.50411.7411-1.6622.88360.0695-0.43460.43080.2175-0.06220.1981-0.207-0.0812-0.0072-0.0886-0.02890.0155-0.081-0.08960.0197-26.8392-38.4203-30.9399
88.3543.0385-1.23443.3437-0.45671.2855-0.17050.47150.2815-0.27720.1863-0.02480.1081-0.0312-0.0158-0.0922-0.02890.0084-0.21220.0033-0.1494-6.9047-33.3071-49.1297
92.81582.994-0.34916.30820.56512.2293-0.11810.3450.1434-0.3034-0.02490.54270.2578-0.34150.1431-0.1012-0.0981-0.1056-0.05150.01490.0208-37.5799-48.5929-43.0603
101.5069-0.1862-0.31361.0956-0.16961.7684-0.1315-0.22750.00680.20490.08980.0053-0.0338-0.20340.0417-0.04690.04430.03110.0394-0.0068-0.0698-14.8673.0077-22.533
112.3076-0.0984-0.43161.12040.07312.2534-0.01210.03120.1918-0.09830.0273-0.0734-0.04470.0572-0.0152-0.0403-0.00750.0344-0.077-0.0002-0.07515.5162.67-40.9229
127.20560.03831.8331.3637-1.30473.15210.02370.3918-0.3932-0.34620.08330.33190.3535-0.4444-0.1069-0.1352-0.0345-0.00680.0321-0.0466-0.0745-28.8711-0.8608-35.5835
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|1 - A|91 }
2X-RAY DIFFRACTION2{ A|92 - A|274 }
3X-RAY DIFFRACTION3{ A|275 - A|333 }
4X-RAY DIFFRACTION4{ B|1 - B|91 }
5X-RAY DIFFRACTION5{ B|92 - B|274 }
6X-RAY DIFFRACTION6{ B|275 - B|333 }
7X-RAY DIFFRACTION7{ C|1 - C|91 }
8X-RAY DIFFRACTION8{ C|92 - C|274 }
9X-RAY DIFFRACTION9{ C|275 - C|333 }
10X-RAY DIFFRACTION10{ D|1 - D|91 }
11X-RAY DIFFRACTION11{ D|92 - D|274 }
12X-RAY DIFFRACTION12{ D|275 - D|333 }

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