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- PDB-4zk5: MAP4K4 in complex with inhibitor GNE-495 -

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Basic information

Entry
Database: PDB / ID: 4zk5
TitleMAP4K4 in complex with inhibitor GNE-495
ComponentsMitogen-activated protein kinase kinase kinase kinase 4
KeywordsTransferase/Transferase Inhibitor / kinase / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


positive regulation of ARF protein signal transduction / creatine kinase activity / positive regulation of keratinocyte migration / positive regulation of focal adhesion disassembly / negative regulation of cell-matrix adhesion / positive regulation of focal adhesion assembly / regulation of MAPK cascade / regulation of JNK cascade / neuron projection morphogenesis / positive regulation of GTPase activity ...positive regulation of ARF protein signal transduction / creatine kinase activity / positive regulation of keratinocyte migration / positive regulation of focal adhesion disassembly / negative regulation of cell-matrix adhesion / positive regulation of focal adhesion assembly / regulation of MAPK cascade / regulation of JNK cascade / neuron projection morphogenesis / positive regulation of GTPase activity / MAPK cascade / microtubule binding / Oxidative Stress Induced Senescence / non-specific serine/threonine protein kinase / positive regulation of cell migration / intracellular signal transduction / protein phosphorylation / focal adhesion / protein serine kinase activity / protein serine/threonine kinase activity / negative regulation of apoptotic process / ATP binding / cytoplasm
Similarity search - Function
Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / Citron homology (CNH) domain / CNH domain / Citron homology (CNH) domain profile. / 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. ...Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / Citron homology (CNH) domain / CNH domain / Citron homology (CNH) domain profile. / 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, ATP binding site / Protein kinases ATP-binding region signature. / 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-4P4 / Mitogen-activated protein kinase kinase kinase kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.89 Å
AuthorsHarris, S.F. / Wu, P. / Coons, M.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis.
Authors: Ndubaku, C.O. / Crawford, T.D. / Chen, H. / Boggs, J.W. / Drobnick, J. / Harris, S.F. / Jesudason, R. / McNamara, E. / Nonomiya, J. / Sambrone, A. / Schmidt, S. / Smyczek, T. / Vitorino, P. ...Authors: Ndubaku, C.O. / Crawford, T.D. / Chen, H. / Boggs, J.W. / Drobnick, J. / Harris, S.F. / Jesudason, R. / McNamara, E. / Nonomiya, J. / Sambrone, A. / Schmidt, S. / Smyczek, T. / Vitorino, P. / Wang, L. / Wu, P. / Yeung, S. / Chen, J. / Chen, K. / Ding, C.Z. / Wang, T. / Xu, Z. / Gould, S.E. / Murray, L.J. / Ye, W.
History
DepositionApr 29, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2016Group: Data collection
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mitogen-activated protein kinase kinase kinase kinase 4
B: Mitogen-activated protein kinase kinase kinase kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,3655
Polymers75,7402
Non-polymers6253
Water1,72996
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2720 Å2
ΔGint-21 kcal/mol
Surface area27060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.352, 89.335, 91.011
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Mitogen-activated protein kinase kinase kinase kinase 4 / HPK/GCK-like kinase HGK / MAPK/ERK kinase kinase kinase 4 / MEKKK 4 / Nck-interacting kinase


Mass: 37870.078 Da / Num. of mol.: 2 / Fragment: kinase domain, UNP residues 2-238
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP4K4, HGK, KIAA0687, NIK / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf9
References: UniProt: O95819, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#4: Chemical ChemComp-4P4 / 8-amino-N-[1-(cyclopropylcarbonyl)azetidin-3-yl]-2-(3-fluorophenyl)-1,7-naphthyridine-5-carboxamide / GNE-495


Mass: 405.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20FN5O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 2.13 Å3/Da / Density % sol: 42.24 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 8.3 / Details: 0.2 M potassium citrate pH 8.3, 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.97945 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 25, 2012
RadiationMonochromator: DOUBLE CRYSTAL Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97945 Å / Relative weight: 1
ReflectionResolution: 2.89→91.011 Å / Num. all: 15054 / Num. obs: 15054 / % possible obs: 99.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 81.23 Å2 / Rpim(I) all: 0.034 / Rrim(I) all: 0.088 / Rsym value: 0.074 / Net I/av σ(I): 8.786 / Net I/σ(I): 17.1 / Num. measured all: 97652
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.89-3.056.60.5281.51423221510.240.5283.399.9
3.05-3.236.30.3572.21285920340.1670.3574.8100
3.23-3.456.80.2043.81327619520.0910.2048.5100
3.45-3.736.70.126.51197917800.0540.1213.599.9
3.73-4.096.30.076101046016520.0360.07618.599.9
4.09-4.576.60.0514.61006115230.0230.0525.899.9
4.57-5.286.60.04117.1892213450.0190.04129.599.9
5.28-6.4660.04715.2691211450.0220.04727.499.8
6.46-9.146.40.03517.259219260.0160.03537.299.9
9.14-91.0115.50.0318.730305460.0140.0344.799.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
PHASERphasing
BUSTER-TNTBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.89→49.7 Å / Cor.coef. Fo:Fc: 0.9169 / Cor.coef. Fo:Fc free: 0.8837 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.43
RfactorNum. reflection% reflectionSelection details
Rfree0.2645 771 5.14 %RANDOM
Rwork0.2129 ---
obs0.2155 15002 99.83 %-
Displacement parametersBiso max: 166.71 Å2 / Biso mean: 71.95 Å2 / Biso min: 33.17 Å2
Baniso -1Baniso -2Baniso -3
1-6.2 Å20 Å20 Å2
2---15.2792 Å20 Å2
3---9.0792 Å2
Refine analyzeLuzzati coordinate error obs: 0.414 Å
Refinement stepCycle: final / Resolution: 2.89→49.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4678 0 43 96 4817
Biso mean--69.4 56.51 -
Num. residues----580
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1722SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes116HARMONIC2
X-RAY DIFFRACTIONt_gen_planes712HARMONIC5
X-RAY DIFFRACTIONt_it4835HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion618SEMIHARMONIC5
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_contact5529SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4835HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6540HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion2.27
X-RAY DIFFRACTIONt_other_torsion20.17
LS refinement shellResolution: 2.89→3.09 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2859 139 5.21 %
Rwork0.2489 2527 -
all0.2507 2666 -
obs--99.83 %

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