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- PDB-4d2t: Structure of MELK in complex with inhibitors -

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Basic information

Entry
Database: PDB / ID: 4d2t
TitleStructure of MELK in complex with inhibitors
ComponentsMATERNAL EMBRYONIC LEUCINE ZIPPER KINASEMELK
KeywordsTRANSFERASE / FRAGMENT BASED DRUG DESIGN / KINASE
Function / homology
Function and homology information


neural precursor cell proliferation / intrinsic apoptotic signaling pathway in response to oxidative stress / hemopoiesis / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / G2/M transition of mitotic cell cycle / cell cortex / cell population proliferation / protein autophosphorylation / non-specific serine/threonine protein kinase ...neural precursor cell proliferation / intrinsic apoptotic signaling pathway in response to oxidative stress / hemopoiesis / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / G2/M transition of mitotic cell cycle / cell cortex / cell population proliferation / protein autophosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / positive regulation of apoptotic process / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / lipid binding / calcium ion binding / ATP binding / membrane / plasma membrane / cytoplasm
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-3I7 / Maternal embryonic leucine zipper kinase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.7 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 15, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 28, 2015Group: Database references
Revision 1.2Mar 18, 2015Group: Refinement description
Revision 2.0Apr 4, 2018Group: Atomic model / Data collection / Category: atom_site / diffrn_source
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _diffrn_source.type
Revision 2.1May 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)164,8558
Polymers163,5054
Non-polymers1,3504
Water7,134396
1
A: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2142
Polymers40,8761
Non-polymers3371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
C: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2142
Polymers40,8761
Non-polymers3371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
B: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2142
Polymers40,8761
Non-polymers3371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,2142
Polymers40,8761
Non-polymers3371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)66.526, 75.410, 79.736
Angle α, β, γ (deg.)86.03, 69.05, 90.03
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 40876.273 Da / Num. of mol.: 4 / Fragment: RESIDUES 1-336 / 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-3I7 / 3-[2-(phenylcarbamoyl)-5-(1H-pyrazol-4-yl)phenoxy]propan-1-aminium


Mass: 337.396 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H21N4O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 396 / 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 22, 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: 2.7→48.5 Å / Num. obs: 39601 / % possible obs: 93.1 % / Observed criterion σ(I): 0.75 / Redundancy: 1.9 % / Biso Wilson estimate: 84.38 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 5.9

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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: 2.7→48.54 Å / Cor.coef. Fo:Fc: 0.9147 / Cor.coef. Fo:Fc free: 0.8563 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.491
RfactorNum. reflection% reflectionSelection details
Rfree0.34 1870 5.07 %RANDOM
Rwork0.2696 ---
obs0.2732 36893 93.14 %-
Displacement parametersBiso mean: 89.482 Å2
Baniso -1Baniso -2Baniso -3
1-8.5337 Å2-1.9684 Å2-7.7593 Å2
2---2.6209 Å2-0.6359 Å2
3----5.9128 Å2
Refine analyzeLuzzati coordinate error obs: 0.674 Å
Refinement stepCycle: LAST / Resolution: 2.7→48.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10279 0 100 396 10775
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0110706HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1114533HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3741SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes253HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1550HARMONIC16
X-RAY DIFFRACTIONt_it10706HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6
X-RAY DIFFRACTIONt_other_torsion22.59
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1335SEMIHARMONIC5
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_contact11861SEMIHARMONIC4
LS refinement shellResolution: 2.7→2.78 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.3179 123 5.19 %
Rwork0.2469 2249 -
all0.2504 2372 -
obs--93.14 %
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)
14.6932-0.0875-3.61140.81610.08135.3691-0.06070.42070.1113-0.3382-0.0288-0.447-0.1360.28440.0895-0.21190.21170.2134-0.23330.12120.18229.8447-0.1651-11.1599
25.0387-1.0016-1.07387.38770.73482.075-0.0097-0.03350.17270.712-0.10860.33320.0684-0.18970.1183-0.03510.09060.1529-0.3071-0.0454-0.0252-10.70024.27676.6559
33.1165-3.8061-1.51210.4112-1.49274.15710.08710.0210.0240.1689-0.1214-0.14520.22040.26180.0343-0.32290.20.0693-0.25180.12740.315820.4232-11.36440.3483
44.0381-0.5305-2.84295.3384-1.36556.4406-0.05830.1982-0.0584-0.712-0.0025-0.2951-0.18370.15880.0608-0.2580.03040.0754-0.1319-0.0086-0.036-2.533-34.1549-20.737
54.15980.0197-1.74443.2647-1.16235.67840.01970.38490.11770.32130.23850.42-0.3827-0.4792-0.2583-0.27740.15860.0837-0.2861-0.00180.0622-22.6052-35.1702-2.0576
63.2901-1.82833.30260.1345-0.34571.69030.0387-0.1518-0.03930.1213-0.1356-0.07470.06960.23690.0969-0.3383-0.03990.05570.12570.18410.219511.4173-39.2354-8.2652
73.7361-1.0372-3.00021.50210.3535.5646-0.1038-0.3031-0.13130.18680.05360.4993-0.1519-0.2420.0502-0.3178-0.19060.1047-0.308-0.04410.3361-28.0626-37.9995-32.6021
86.57682.1537-1.847.3419-1.18081.05660.12240.21570.5027-0.6849-0.1571-0.27460.11540.23360.03480.13710.01850.1309-0.30260.018-0.0254-7.1326-33.3072-49.7337
91.62043.08940.18320.40091.92210.81410.04830.12210.0935-0.095-0.10280.14270.0807-0.16050.0546-0.0419-0.1935-0.0479-0.3061-0.05220.2731-38.4184-48.838-44.2353
104.9058-0.956-2.29144.98522.37148.1765-0.0507-0.6396-0.08830.63920.02270.1559-0.061-0.17290.028-0.28620.01520.0651-0.1136-0.0177-0.048-15.29613.738-22.9576
115.9254-0.3828-3.35013.37190.66517.08150.0327-0.3330.3573-0.37230.1404-0.4543-0.3960.5711-0.1731-0.2771-0.07740.101-0.3189-0.0710.04054.39873.044-41.2053
122.12613.2982.46431.30920.32372.4631-0.00150.03730.0015-0.0349-0.08680.28770.045-0.40970.0883-0.33450.01220.06980.2831-0.16780.2904-28.9288-1.8508-34.8958
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND RESIDUES 1 TO 91
2X-RAY DIFFRACTION2CHAIN A AND RESIDUES 92 TO 274
3X-RAY DIFFRACTION3CHAIN A AND RESIDUES 275 TO 333
4X-RAY DIFFRACTION4CHAIN B AND RESIDUES 0 TO 91
5X-RAY DIFFRACTION5CHAIN B AND RESIDUES 92 TO 274
6X-RAY DIFFRACTION6CHAIN B AND RESIDUES 275 TO 333
7X-RAY DIFFRACTION7CHAIN C AND RESIDUES 1 TO 91
8X-RAY DIFFRACTION8CHAIN C AND RESIDUES 92 TO 274
9X-RAY DIFFRACTION9CHAIN C AND RESIDUES 275 TO 333
10X-RAY DIFFRACTION10CHAIN D AND RESIDUES 3 TO 91
11X-RAY DIFFRACTION11CHAIN D AND RESIDUES 92 TO 274
12X-RAY DIFFRACTION12CHAIN D AND RESIDUES 275 TO 333

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