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- PDB-4d2v: Structure of MELK in complex with inhibitors -

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Basic information

Entry
Database: PDB / ID: 4d2v
TitleStructure of MELK in complex with inhibitors
ComponentsMATERNAL EMBRYONIC LEUCINE ZIPPER KINASEMELK
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-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 / lipid binding / apoptotic process / 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-45R / Maternal embryonic leucine zipper kinase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.45 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 / Structure summary
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)164,9598
Polymers163,5054
Non-polymers1,4544
Water9,800544
1
B: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
C: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,4794
Polymers81,7532
Non-polymers7272
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2590 Å2
ΔGint-11.6 kcal/mol
Surface area28710 Å2
MethodPISA
2
A: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
D: MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,4794
Polymers81,7532
Non-polymers7272
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2440 Å2
ΔGint-11.4 kcal/mol
Surface area28530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.650, 75.860, 79.070
Angle α, β, γ (deg.)86.08, 69.45, 89.87
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 / 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-45R / 7-{[2-methoxy-4-(1H-pyrazol-4-yl)benzoyl]amino}-2,3,4,5-tetrahydro-1H-3-benzazepinium


Mass: 363.433 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H23N4O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 544 / 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: Oct 15, 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: 2.45→48 Å / Num. obs: 53154 / % possible obs: 94.6 % / Observed criterion σ(I): 0.75 / Redundancy: 1.9 % / Biso Wilson estimate: 64.82 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 4.7

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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: 2.45→48.69 Å / Cor.coef. Fo:Fc: 0.9082 / Cor.coef. Fo:Fc free: 0.8576 / SU R Cruickshank DPI: 0.971 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.885 / SU Rfree Blow DPI: 0.405 / SU Rfree Cruickshank DPI: 0.415
RfactorNum. reflection% reflectionSelection details
Rfree0.357 2512 5 %RANDOM
Rwork0.2913 ---
obs0.2945 50274 94.58 %-
Displacement parametersBiso mean: 69.136 Å2
Baniso -1Baniso -2Baniso -3
1-4.2381 Å2-2.2724 Å2-4.4884 Å2
2---2.1992 Å20.2321 Å2
3----2.0389 Å2
Refine analyzeLuzzati coordinate error obs: 0.628 Å
Refinement stepCycle: LAST / Resolution: 2.45→48.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10280 0 108 544 10932
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.01110742HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1714604HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3762SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes252HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1554HARMONIC16
X-RAY DIFFRACTIONt_it10742HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.72
X-RAY DIFFRACTIONt_other_torsion22.12
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1334SEMIHARMONIC5
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_contact11927SEMIHARMONIC4
LS refinement shellResolution: 2.45→2.51 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3273 170 4.67 %
Rwork0.2562 3471 -
all0.2594 3641 -
obs--94.58 %
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)
12.32621.3504-1.38990.68131.29125.2418-0.16960.25190.1952-0.10730.35220.1653-0.38180.0133-0.1827-0.23360.15610.0555-0.10880.11920.08559.0083-0.7111-12.5086
27.183-2.2834-2.41413.03671.09053.40090.0164-0.47780.53330.35850.19330.0168-0.0512-0.102-0.2097-0.18450.14780.1282-0.29480.0331-0.0273-11.08953.95236.046
31.4599-2.90151.23395.70480.28275.36610.1585-0.14610.03380.1634-0.0917-0.09550.34590.261-0.0668-0.28110.19640.121-0.14490.11570.18520.1245-11.4997-0.5546
44.2941.1904-3.43642.0341-1.96895.6816-0.24940.6167-0.4102-0.36080.4058-0.4543-0.14560.1775-0.1564-0.2818-0.11820.0848-0.0125-0.0606-0.0125-3.0428-34.3351-20.8177
53.18910.2607-1.1022.143-0.18683.2824-0.0423-0.09790.01060.30750.08980.418-0.1238-0.0992-0.0475-0.25860.07770.0809-0.2834-0.00480.1193-23.2331-35.432-2.4881
62.3726-0.12932.65141.53430.748-0.4443-0.0532-0.0571-0.11440.1469-0.081-0.12440.05540.33370.1342-0.3314-0.09650.06980.23340.20020.256510.945-39.665-8.3394
75.64210.0797-2.47541.4699-1.37335.5092-0.134-0.25250.1865-0.04040.1270.2244-0.28650.03760.007-0.3031-0.07910.0104-0.1825-0.0510.1006-26.9928-38.7794-30.9976
88.10183.108-1.35375.1036-0.14682.7241-0.22470.57450.3247-0.53190.2224-0.191-0.03160.01170.0022-0.2853-0.04850.0813-0.30710.0038-0.0056-7.3146-32.9395-49.3133
92.46173.95243.68564.41611.68962.64440.0540.12670.0363-0.05720.03710.1330.1592-0.3593-0.0911-0.3493-0.19710.0228-0.0285-0.08090.1341-38.1105-48.984-42.8862
104.6124-1.473-2.57832.56381.64266.5294-0.2714-0.477-0.24830.43510.37640.3683-0.23260.0069-0.1051-0.28040.10690.0843-0.0360.0286-0.0192-14.7073.7417-22.6969
114.00240.1083-1.58142.6915-0.1323.78240.0906-0.14230.2641-0.18770.0106-0.2064-0.29010.2332-0.1012-0.2967-0.01420.0818-0.2103-0.03110.08585.27142.9936-41.0111
123.21433.57511.73920.56320.7102-0.9977-0.08190.1893-0.092-0.27150.02620.1678-0.0377-0.29070.0557-0.34240.06710.05720.1616-0.16830.2767-28.9464-1.7334-34.6652
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND RESIDUES 0 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 2 TO 91
5X-RAY DIFFRACTION5CHAIN B AND RESIDUES 275 TO 333
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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