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- PDB-4u43: MAP4K4 in complex with inhibitor (compound 6) -

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Basic information

Entry
Database: PDB / ID: 4u43
TitleMAP4K4 in complex with inhibitor (compound 6)
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-3D8 / Mitogen-activated protein kinase kinase kinase kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.18 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 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.3Dec 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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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)75,9513
Polymers75,7402
Non-polymers2111
Water3,747208
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3380 Å2
ΔGint-16 kcal/mol
Surface area26250 Å2
MethodPISA
2
A: Mitogen-activated protein kinase kinase kinase kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0812
Polymers37,8701
Non-polymers2111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
B: Mitogen-activated protein kinase kinase kinase kinase 4


Theoretical massNumber of molelcules
Total (without water)37,8701
Polymers37,8701
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.492, 80.643, 102.335
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-3D8 / N-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine


Mass: 211.223 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H9N5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 208 / 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: 2.06 Å3/Da / Density % sol: 40.19 %
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-D / Wavelength: 1.1001 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 17, 2010
RadiationMonochromator: KOHZU Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1001 Å / Relative weight: 1
ReflectionResolution: 2.18→50 Å / Num. obs: 33286 / % possible obs: 99.9 % / Redundancy: 6.1 % / Biso Wilson estimate: 47.76 Å2 / Rmerge(I) obs: 0.064 / Χ2: 1.034 / Net I/av σ(I): 26.119 / Net I/σ(I): 9.3 / Num. measured all: 203453
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.18-2.266.20.56532621.025100
2.26-2.356.20.39632851.011100
2.35-2.466.20.28932761.046100
2.46-2.586.20.23232861.048100
2.58-2.756.20.16332851.029100
2.75-2.966.20.11333241.046100
2.96-3.266.20.07733351.018100
3.26-3.736.10.07333151.015100
3.73-4.760.04933911.052100
4.7-505.80.03535271.04899.5

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
PDB_EXTRACT3.14data extraction
BUSTER2.9.1refinement
RefinementResolution: 2.18→29.08 Å / SU R Cruickshank DPI: 0.263 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.27 / SU Rfree Blow DPI: 0.204 / SU Rfree Cruickshank DPI: 0.205
RfactorNum. reflection% reflectionSelection details
Rfree0.2425 1703 5.13 %RANDOM
Rwork0.1964 ---
obs0.1987 33223 99.9 %-
Displacement parametersBiso max: 156.08 Å2 / Biso mean: 58.13 Å2 / Biso min: 27.13 Å2
Baniso -1Baniso -2Baniso -3
1--10.733 Å20 Å20 Å2
2--12.0563 Å20 Å2
3----1.3233 Å2
Refine analyzeLuzzati coordinate error obs: 0.289 Å
Refinement stepCycle: final / Resolution: 2.18→29.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4754 0 16 208 4978
Biso mean--46.35 53.03 -
Num. residues----589
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1739SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes125HARMONIC2
X-RAY DIFFRACTIONt_gen_planes708HARMONIC5
X-RAY DIFFRACTIONt_it4909HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion628SEMIHARMONIC5
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_contact5815SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4909HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg6641HARMONIC21.1
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion20.3
LS refinement shellResolution: 2.18→2.25 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.2876 133 4.71 %
Rwork0.2378 2693 -
all0.24 2826 -
obs--99.9 %

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