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- PDB-3pp1: Crystal Structure of the Human Mitogen-activated protein kinase k... -

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Basic information

Entry
Database: PDB / ID: 3pp1
TitleCrystal Structure of the Human Mitogen-activated protein kinase kinase 1 (MEK 1) in complex with ligand and MgATP
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase domain / Kinase / ATP binding / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / type B pancreatic cell proliferation / labyrinthine layer development / MAP-kinase scaffold activity / cerebellar cortex formation / Signaling by MAP2K mutants ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / type B pancreatic cell proliferation / labyrinthine layer development / MAP-kinase scaffold activity / cerebellar cortex formation / Signaling by MAP2K mutants / regulation of Golgi inheritance / trachea formation / regulation of early endosome to late endosome transport / Negative feedback regulation of MAPK pathway / regulation of stress-activated MAPK cascade / positive regulation of axonogenesis / Frs2-mediated activation / protein kinase activator activity / ERBB2-ERBB3 signaling pathway / face development / endodermal cell differentiation / MAPK3 (ERK1) activation / Bergmann glial cell differentiation / MAP kinase kinase activity / thyroid gland development / Uptake and function of anthrax toxins / Schwann cell development / keratinocyte differentiation / ERK1 and ERK2 cascade / myelination / protein serine/threonine/tyrosine kinase activity / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / insulin-like growth factor receptor signaling pathway / thymus development / Signal transduction by L1 / cell motility / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / positive regulation of protein serine/threonine kinase activity / neuron differentiation / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / chemotaxis / MAPK cascade / cellular senescence / Signaling by BRAF and RAF1 fusions / late endosome / heart development / scaffold protein binding / protein tyrosine kinase activity / positive regulation of ERK1 and ERK2 cascade / early endosome / protein kinase activity / negative regulation of cell population proliferation / protein phosphorylation / focal adhesion / protein serine kinase activity / centrosome / protein serine/threonine kinase activity / positive regulation of gene expression / positive regulation of DNA-templated transcription / Golgi apparatus / endoplasmic reticulum / signal transduction / mitochondrion / ATP binding / nucleus / plasma membrane / cytosol
Similarity search - Function
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. ...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
ACETATE ION / ADENOSINE-5'-TRIPHOSPHATE / Chem-IZG / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsDougan, D.R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer.
Authors: Dong, Q. / Dougan, D.R. / Gong, X. / Halkowycz, P. / Jin, B. / Kanouni, T. / O'Connell, S.M. / Scorah, N. / Shi, L. / Wallace, M.B. / Zhou, F.
History
DepositionNov 23, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 23, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Feb 21, 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_asym_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_asym_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_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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

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Assembly

Deposited unit
A: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7355
Polymers36,6401
Non-polymers1,0954
Water1,22568
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)82.086, 82.086, 129.254
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number171
Space group name H-MP62
Components on special symmetry positions
IDModelComponents
11A-619-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Dual specificity mitogen-activated protein kinase kinase 1 / MAP kinase kinase 1 / MAPKK 1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK 1


Mass: 36640.219 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, Mapk/erk kinase 1, MEK1, PRKMK1 / Plasmid: pet21a(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 DE3
References: UniProt: Q02750, mitogen-activated protein kinase kinase

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Non-polymers , 5 types, 72 molecules

#2: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-IZG / 3-[(2R)-2,3-dihydroxypropyl]-6-fluoro-5-[(2-fluoro-4-iodophenyl)amino]-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione / MEK inhibitor


Mass: 504.227 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15F2IN4O4 / Comment: inhibitor*YM
#5: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 68 / 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: 3.43 Å3/Da / Density % sol: 64.15 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 10% MPD, 0.1M MES, pH 6.0, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 12, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 13651 / % possible obs: 100 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.081 / Net I/σ(I): 17
Reflection shellResolution: 2.7→2.75 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.764 / Mean I/σ(I) obs: 1.9 / % possible all: 100

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Processing

Software
NameVersionClassification
Blu-Icedata collection
MOLREPphasing
REFMAC5.5.0109refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→30 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.93 / SU B: 23.238 / SU ML: 0.211 / Cross valid method: THROUGHOUT / ESU R Free: 0.261 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21941 673 5 %RANDOM
Rwork0.18202 ---
obs0.18379 12915 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 61.634 Å2
Baniso -1Baniso -2Baniso -3
1-0.63 Å20.31 Å20 Å2
2--0.63 Å20 Å2
3----0.94 Å2
Refinement stepCycle: LAST / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2279 0 64 68 2411
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222397
X-RAY DIFFRACTIONr_bond_other_d0.0020.023
X-RAY DIFFRACTIONr_angle_refined_deg1.312.013240
X-RAY DIFFRACTIONr_angle_other_deg1.11536
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4795289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.124.5100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.30915430
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5391512
X-RAY DIFFRACTIONr_chiral_restr0.0870.2352
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211802
X-RAY DIFFRACTIONr_mcbond_it1.97121450
X-RAY DIFFRACTIONr_mcangle_it3.42732339
X-RAY DIFFRACTIONr_scbond_it2.2732947
X-RAY DIFFRACTIONr_scangle_it3.7323901
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.298 53 -
Rwork0.309 933 -
obs--99.9 %
Refinement TLS params.Method: refined / Origin x: -30.3047 Å / Origin y: 21.602 Å / Origin z: -0.0921 Å
111213212223313233
T0.1318 Å2-0.0656 Å2-0.0609 Å2-0.0458 Å2-0.0076 Å2--0.1737 Å2
L1.3769 °20.0505 °2-0.3641 °2-1.4367 °20.339 °2--4.2839 °2
S0.1008 Å °0.0286 Å °-0.3734 Å °0.1583 Å °-0.0656 Å °-0.1786 Å °-0.0325 Å °0.1397 Å °-0.0352 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A61 - 146
2X-RAY DIFFRACTION1A147 - 382
3X-RAY DIFFRACTION1A400
4X-RAY DIFFRACTION1A500

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