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- PDB-4u45: MAP4K4 in complex with inhibitor (compound 25) -

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Basic information

Entry
Database: PDB / ID: 4u45
TitleMAP4K4 in complex with inhibitor (compound 25)
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 / MAP kinase kinase kinase kinase activity / creatine kinase activity / positive regulation of hippo signaling / positive regulation of keratinocyte migration / positive regulation of focal adhesion disassembly / negative regulation of cell-matrix adhesion / regulation of MAPK cascade / positive regulation of focal adhesion assembly / regulation of JNK cascade ...positive regulation of ARF protein signal transduction / MAP kinase kinase kinase kinase activity / creatine kinase activity / positive regulation of hippo signaling / positive regulation of keratinocyte migration / positive regulation of focal adhesion disassembly / negative regulation of cell-matrix adhesion / regulation of MAPK cascade / positive regulation of focal adhesion assembly / 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 / intracellular signal transduction / positive regulation of cell migration / protein phosphorylation / protein serine kinase activity / focal adhesion / 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 / CNH domain / Citron homology (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 ...: / Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / CNH domain / Citron homology (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-3DC / Mitogen-activated protein kinase kinase kinase kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.58 Å
AuthorsHarris, S.F. / Wu, P. / Coons, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors.
Authors: Wang, L. / Stanley, M. / Boggs, J.W. / Crawford, T.D. / Bravo, B.J. / Giannetti, A.M. / Harris, S.F. / Magnuson, S.R. / Nonomiya, J. / Schmidt, S. / Wu, P. / Ye, W. / Gould, S.E. / Murray, L. ...Authors: Wang, L. / Stanley, M. / Boggs, J.W. / Crawford, T.D. / Bravo, B.J. / Giannetti, A.M. / Harris, S.F. / Magnuson, S.R. / Nonomiya, J. / Schmidt, S. / Wu, P. / Ye, W. / Gould, S.E. / Murray, L.J. / Ndubaku, C.O. / Chen, H.
History
DepositionJul 23, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 3, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 1, 2014Group: Database references
Revision 1.2Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / refine_hist
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)76,2616
Polymers75,7402
Non-polymers5214
Water3,711206
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2830 Å2
ΔGint-32 kcal/mol
Surface area26930 Å2
MethodPISA
2
A: Mitogen-activated protein kinase kinase kinase kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1964
Polymers37,8701
Non-polymers3263
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
B: Mitogen-activated protein kinase kinase kinase kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0652
Polymers37,8701
Non-polymers1951
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)79.915, 89.018, 91.396
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 2-328)
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.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-3DC / 6-(1H-pyrazol-4-yl)-N-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine


Mass: 277.284 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H11N7
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 206 / 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: 2.15 Å3/Da / Density % sol: 42.69 %
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: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Mar 12, 2014
RadiationMonochromator: Diamond (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.57→91.4 Å / Num. obs: 21377 / % possible obs: 99.9 % / Redundancy: 6 % / Biso Wilson estimate: 67.41 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.025 / Net I/σ(I): 24.9 / Num. measured all: 129087
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.57-2.876.20.4524.63679359790.9330.194100
5.75-91.45.50.02160.511310204810.00999.4

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Processing

Software
NameVersionClassification
XDS0.1.27data reduction
Aimlessdata scaling
PDB_EXTRACT3.14data extraction
BUSTER2.11.4refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.58→63.77 Å / Cor.coef. Fo:Fc: 0.9356 / Cor.coef. Fo:Fc free: 0.9091 / SU R Cruickshank DPI: 0.992 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.81 / SU Rfree Blow DPI: 0.306 / SU Rfree Cruickshank DPI: 0.304
RfactorNum. reflection% reflectionSelection details
Rfree0.2441 1077 5.1 %RANDOM
Rwork0.1947 ---
obs0.1972 21109 99.86 %-
Displacement parametersBiso max: 165.62 Å2 / Biso mean: 64.8 Å2 / Biso min: 25.84 Å2
Baniso -1Baniso -2Baniso -3
1-11.6769 Å20 Å20 Å2
2---9.9499 Å20 Å2
3----1.727 Å2
Refine analyzeLuzzati coordinate error obs: 0.336 Å
Refinement stepCycle: final / Resolution: 2.58→63.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4713 0 36 206 4955
Biso mean--67.52 53.81 -
Num. residues----584
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1729SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes120HARMONIC2
X-RAY DIFFRACTIONt_gen_planes719HARMONIC5
X-RAY DIFFRACTIONt_it4866HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion624SEMIHARMONIC5
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_contact5741SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4866HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg6579HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.8
X-RAY DIFFRACTIONt_other_torsion20.63
LS refinement shellResolution: 2.58→2.71 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2979 143 5.17 %
Rwork0.2211 2621 -
all0.2247 2764 -
obs--99.86 %

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