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

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Basic information

Entry
Database: PDB / ID: 4ump
TitleStructure of MELK in complex with inhibitors
ComponentsMATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
KeywordsTRANSFERASE
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 / protein autophosphorylation / cell population proliferation / 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 / protein autophosphorylation / cell population proliferation / non-specific serine/threonine protein kinase / positive regulation of apoptotic process / protein serine kinase activity / protein serine/threonine kinase activity / lipid binding / calcium ion binding / apoptotic process / 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
3-(isoquinolin-7-yl)prop-2-yn-1-ol / Maternal embryonic leucine zipper kinase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.3 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 20, 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)164,2388
Polymers163,5054
Non-polymers7334
Water10,160564
1
A: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
D: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,1194
Polymers81,7532
Non-polymers3662
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2370 Å2
ΔGint-9.7 kcal/mol
Surface area28200 Å2
MethodPISA
2
B: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
C: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,1194
Polymers81,7532
Non-polymers3662
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2660 Å2
ΔGint-7.9 kcal/mol
Surface area28040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.822, 74.968, 77.088
Angle α, β, γ (deg.)86.47, 70.06, 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-5QM / 3-(isoquinolin-7-yl)prop-2-yn-1-ol


Mass: 183.206 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H9NO
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 564 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsPOINT MUTATIONS EXIST IN THE SEQUENCE, IN ADDITION TO THE HIS TAG

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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 IMAGE PLATE RAXIS / Detector: IMAGE PLATE / Date: May 2, 2010 / 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: 2.3→50 Å / Num. obs: 61286 / % possible obs: 95.8 % / Observed criterion σ(I): 0.8 / Redundancy: 1.95 % / Biso Wilson estimate: 62.93 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 5.7

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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: 2.3→50.38 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.8845 / SU R Cruickshank DPI: 0.467 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.448 / SU Rfree Blow DPI: 0.285 / SU Rfree Cruickshank DPI: 0.292
RfactorNum. reflection% reflectionSelection details
Rfree0.291 2989 5.09 %RANDOM
Rwork0.235 ---
obs0.2378 58731 95.71 %-
Displacement parametersBiso mean: 61.084 Å2
Baniso -1Baniso -2Baniso -3
1-5.4801 Å2-1.6477 Å23.8462 Å2
2---1.7019 Å2-2.8855 Å2
3----3.7782 Å2
Refine analyzeLuzzati coordinate error obs: 0.424 Å
Refinement stepCycle: LAST / Resolution: 2.3→50.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10268 0 56 564 10888
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.01110612HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9414365HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3724SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes254HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1533HARMONIC16
X-RAY DIFFRACTIONt_it10612HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.91
X-RAY DIFFRACTIONt_other_torsion21.02
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1338SEMIHARMONIC5
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_contact12136SEMIHARMONIC4
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3176 232 5.48 %
Rwork0.2594 4001 -
all0.2625 4233 -
obs--95.71 %
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)
11.86430.4805-1.07450.16721.19931.3889-0.00720.00580.0115-0.0272-0.0131-0.0198-0.01250.03650.0203-0.08480.16160.02220.02360.0649-0.01058.7193-0.8056-12.2074
22.9857-0.7045-0.21570.88980.13910.2689-0.0122-0.11850.040.02170.05570.04010.0032-0.0101-0.04350.00530.13480.0538-0.00970.0454-0.129-11.28173.72855.9685
30.7762-1.74790.82260.1176-0.81810.02990.0055-0.0242-0.01750.0308-0.0133-0.00570.02120.03760.0078-0.04490.1694-0.08580.05370.092-0.017519.6279-11.7041-0.8127
40.5781-0.0654-1.32310.0666-0.34421.5158-0.0059-0.01080.0066-0.0315-0.0120.0045-0.03570.02660.018-0.09580.0308-0.02380.01590.04070.0372-2.954-33.993-20.9811
50.38650.2516-0.76560.8329-0.34541.7646-0.0076-0.02670.02760.01970.02220.0795-0.0351-0.0009-0.0146-0.12940.0968-0.033-0.09260.00060.1008-23.1342-35.124-2.7295
60.78520.03580.936-0.0513-0.7278-0.6178-0.0035-0.0213-0.00510.02150.0102-0.00030.00180.0255-0.0067-0.1037-0.0093-0.06960.08890.0770.002310.8115-40.2229-9.0877
71.4477-0.4919-0.50860.1556-0.34431.00490.0029-0.02290.00320.02670.00140.01050.0124-0.0033-0.0043-0.109-0.025-0.0258-0.0220.02330.0774-26.8451-38.5776-30.9868
81.80920.5935-0.06140.2839-0.08340.9701-0.04810.1501-0.0811-0.0210.0923-0.0133-0.0214-0.0324-0.0442-0.03510.0521-0.0418-0.0732-0.03380.0128-6.6808-32.6362-48.6724
91.01151.89181.23260.24541.1555-0.2528-0.00350.0236-0.0087-0.0186-0.01210.01650.0141-0.01580.0156-0.0845-0.1999-0.14190.0282-0.08140.0181-37.511-48.4995-42.7702
100.7614-0.6507-1.30750.04150.30091.01080.0034-0.01370.01720.0546-0.0263-0.0062-0.0245-0.06870.0229-0.11440.04680.05380.1246-0.0226-0.0551-14.85534.253-22.672
111.22360.5434-0.70681.3624-0.14312.4182-0.0274-0.00440.0391-0.05580.0412-0.0165-0.09970.0891-0.0138-0.11020.0381-0.0027-0.0040.024-0.06345.16773.1355-40.6802
120.8767-0.11160.69930.06510.2259-0.1093-0.0007-0.00390.0026-0.0123-0.0020.00270.0053-0.0070.0028-0.07650.0228-0.040.0951-0.0545-0.0234-28.4658-2.0591-34.078

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