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- PDB-4obo: MAP4K4 in complex with inhibitor (compound 22), 6-(3-CHLOROPHENYL... -

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Basic information

Entry
Database: PDB / ID: 4obo
TitleMAP4K4 in complex with inhibitor (compound 22), 6-(3-CHLOROPHENYL)QUINAZOLIN-4-AMINE
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
6-(3-chlorophenyl)quinazolin-4-amine / Mitogen-activated protein kinase kinase kinase kinase 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / molecular replacement / Resolution: 2.1 Å
AuthorsHarris, S.F. / Wu, P. / Coons, M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of Selective 4-Amino-pyridopyrimidine Inhibitors of MAP4K4 Using Fragment-Based Lead Identification and Optimization.
Authors: Crawford, T.D. / Ndubaku, C.O. / Chen, H. / Boggs, J.W. / Bravo, B.J. / Delatorre, K. / Giannetti, A.M. / Gould, S.E. / Harris, S.F. / Magnuson, S.R. / McNamara, E. / Murray, L.J. / ...Authors: Crawford, T.D. / Ndubaku, C.O. / Chen, H. / Boggs, J.W. / Bravo, B.J. / Delatorre, K. / Giannetti, A.M. / Gould, S.E. / Harris, S.F. / Magnuson, S.R. / McNamara, E. / Murray, L.J. / Nonomiya, J. / Sambrone, A. / Schmidt, S. / Smyczek, T. / Stanley, M. / Vitorino, P. / Wang, L. / West, K. / Wu, P. / Ye, W.
History
DepositionJan 7, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 23, 2014Provider: repository / Type: Initial release
Revision 1.1May 7, 2014Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_ref_seq_dif.details / _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: 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)76,2376
Polymers75,7402
Non-polymers4974
Water4,143230
1
A: Mitogen-activated protein kinase kinase kinase kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3444
Polymers37,8701
Non-polymers4743
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase kinase kinase kinase 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8932
Polymers37,8701
Non-polymers231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2920 Å2
ΔGint-35 kcal/mol
Surface area27200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)80.000, 81.651, 93.296
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / MEK kinase kinase 4 / MEKKK 4 / Nck- ...HPK/GCK-like kinase HGK / MAPK/ERK kinase kinase kinase 4 / MEK kinase kinase 4 / MEKKK 4 / Nck-interacting kinase


Mass: 37870.078 Da / Num. of mol.: 2 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HGK, KIAA0687, MAP4K4, NIK / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
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.: 2 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-2QV / 6-(3-chlorophenyl)quinazolin-4-amine


Mass: 255.702 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H10ClN3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 230 / 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: 2.01 Å3/Da / Density % sol: 38.85 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 8.3
Details: 0.2 M potassium citrate pH 8.3, 20% PEG 3350, vapor diffusion, sitting drop, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 19, 2011
RadiationMonochromator: DOUBLE CRYSTAL Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 36271 / % possible obs: 99.9 % / Redundancy: 7.1 % / Biso Wilson estimate: 39.04 Å2 / Rmerge(I) obs: 0.087 / Χ2: 1.057 / Net I/σ(I): 13.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.1-2.187.20.55535670.9491100
2.18-2.267.20.51535691.3691100
2.26-2.377.30.33335611.071100
2.37-2.497.30.22535991.0911100
2.49-2.657.30.17135941.091100
2.65-2.857.30.1436011.0621100
2.85-3.147.20.10436250.978199.9
3.14-3.5970.08336300.971100
3.59-4.526.40.06636771.002199.9
4.52-506.30.05238480.97199.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3 Å40.3 Å
Translation3 Å40.3 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASER2.1.4phasing
BUSTER-TNTrefinement
PDB_EXTRACT3.14data extraction
Blu-Icedata collection
HKL-2000data reduction
HKL-2000data scaling
BUSTER2.9.7refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.1→40.3 Å / Cor.coef. Fo:Fc: 0.9407 / Cor.coef. Fo:Fc free: 0.9252 / Occupancy max: 1 / Occupancy min: 0.3 / SU R Cruickshank DPI: 0.239 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.2352 1804 4.99 %RANDOM
Rwork0.2093 ---
obs0.2106 36153 99.47 %-
Displacement parametersBiso max: 141.07 Å2 / Biso mean: 47.1177 Å2 / Biso min: 13.89 Å2
Baniso -1Baniso -2Baniso -3
1-6.8553 Å20 Å20 Å2
2--1.2536 Å20 Å2
3----8.1089 Å2
Refine analyzeLuzzati coordinate error obs: 0.289 Å
Refinement stepCycle: LAST / Resolution: 2.1→40.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4623 0 32 230 4885
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1691SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes121HARMONIC2
X-RAY DIFFRACTIONt_gen_planes681HARMONIC5
X-RAY DIFFRACTIONt_it4775HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion611SEMIHARMONIC5
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_contact5652SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4775HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6453HARMONIC21.05
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion19.49
LS refinement shellResolution: 2.1→2.16 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.2725 128 4.54 %
Rwork0.2356 2689 -
all0.2372 2817 -
obs--99.47 %

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