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- PDB-4u44: MAP4K4 in complex with inhibitor (compound 16) -

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Basic information

Entry
Database: PDB / ID: 4u44
TitleMAP4K4 in complex with inhibitor (compound 16)
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-3D9 / Mitogen-activated protein kinase kinase kinase kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.43 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 1.2Aug 23, 2017Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: citation / diffrn_detector ...citation / diffrn_detector / entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / pdbx_validate_symm_contact / software
Item: _citation.journal_id_CSD / _diffrn_detector.detector ..._citation.journal_id_CSD / _diffrn_detector.detector / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation / _pdbx_validate_symm_contact.auth_seq_id_1 / _pdbx_validate_symm_contact.auth_seq_id_2 / _software.classification / _software.version
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

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)76,2465
Polymers75,7402
Non-polymers5063
Water1,874104
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2690 Å2
ΔGint-21 kcal/mol
Surface area26960 Å2
MethodPISA
2
A: Mitogen-activated protein kinase kinase kinase kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3764
Polymers37,8701
Non-polymers5063
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)80.239, 87.975, 92.392
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-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
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-3D9 / 6-phenyl-N-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine


Mass: 287.319 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H13N5
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 104 / 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: 42.86 %
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: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 5, 2014
RadiationMonochromator: DOUBLE CRYSTAL Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.42→87.97 Å / Num. obs: 25406 / % possible obs: 99.8 % / Redundancy: 6.6 % / CC1/2: 1 / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.017 / Net I/σ(I): 29.5 / Num. measured all: 166737
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.42-2.716.80.4364.14800071050.9520.17999.9
5.42-87.976.20.01682.915016243310.00799.4

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACT3.14data extraction
PHENIX1.8.2_1309refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.43→40.9 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 1.2 / Phase error: 27.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2418 2407 5.09 %
Rwork0.1976 --
obs0.1998 25406 99.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 129.16 Å2 / Biso mean: 67.0322 Å2 / Biso min: 33.63 Å2
Refinement stepCycle: final / Resolution: 2.43→40.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4696 0 35 104 4835
Biso mean--60.58 51.29 -
Num. residues----582
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0064886
X-RAY DIFFRACTIONf_angle_d0.9686610
X-RAY DIFFRACTIONf_chiral_restr0.071710
X-RAY DIFFRACTIONf_plane_restr0.004850
X-RAY DIFFRACTIONf_dihedral_angle_d15.7671845
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 17

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.43-2.47960.36081390.283726312770100
2.4796-2.53350.30951440.27426492793100
2.5335-2.59250.3241340.25952665279999
2.5925-2.65730.37421470.236126422789100
2.6573-2.72910.32261380.25126242762100
2.7291-2.80940.34561540.2632625277999
2.8094-2.90010.31291280.247826892817100
2.9001-3.00370.33261160.22552654277099
3.0037-3.12390.26341570.23362609276699
3.1239-3.2660.28111610.222626332794100
3.266-3.43810.26021240.22132654277899
3.4381-3.65340.25231720.20182617278999
3.6534-3.93530.21061360.1832634277099
3.9353-4.33090.22071390.170826502789100
4.3309-4.95670.21011460.16562636278299
4.9567-6.24140.21031330.17562634276799
6.2414-40.90590.19161390.17112629276899

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