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- PDB-4ark: CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN MAP KINASE KIN... -

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Entry
Database: PDB / ID: 4ark
TitleCRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN MAP KINASE KINASE 1 (MEK1) IN COMPLEX WITH A SMALL MOLECULE INHIBITOR AND ADP
ComponentsDUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1
KeywordsTRANSFERASE / KINASE / INHIBITOR
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / positive regulation of endodermal cell differentiation / regulation of vascular associated smooth muscle contraction / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development / MAP-kinase scaffold activity / positive regulation of muscle contraction ...epithelial cell proliferation involved in lung morphogenesis / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / positive regulation of endodermal cell differentiation / regulation of vascular associated smooth muscle contraction / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development / MAP-kinase scaffold activity / positive regulation of muscle contraction / labyrinthine layer development / regulation of axon regeneration / cerebellar cortex formation / melanosome transport / type B pancreatic cell proliferation / central nervous system neuron differentiation / Signaling by MAP2K mutants / vesicle transport along microtubule / positive regulation of axonogenesis / positive regulation of Ras protein signal transduction / regulation of Golgi inheritance / mitogen-activated protein kinase kinase kinase binding / triglyceride homeostasis / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / Frs2-mediated activation / MAPK3 (ERK1) activation / ERBB2-ERBB3 signaling pathway / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / endodermal cell differentiation / face development / MAP kinase kinase activity / positive regulation of ATP biosynthetic process / Bergmann glial cell differentiation / Uptake and function of anthrax toxins / thyroid gland development / protein kinase activator activity / positive regulation of protein serine/threonine kinase activity / response to axon injury / Schwann cell development / keratinocyte differentiation / MAP3K8 (TPL2)-dependent MAPK1/3 activation / neuron projection morphogenesis / ERK1 and ERK2 cascade / myelination / positive regulation of autophagy / protein serine/threonine/tyrosine kinase activity / dendrite cytoplasm / insulin-like growth factor receptor signaling pathway / response to glucocorticoid / thymus development / protein serine/threonine kinase activator activity / Signal transduction by L1 / cell motility / positive regulation of transcription elongation by RNA polymerase II / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / small GTPase binding / chemotaxis / 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 / Signaling by BRAF and RAF1 fusions / cellular senescence / MAPK cascade / late endosome / heart development / scaffold protein binding / protein tyrosine kinase activity / cell cortex / perikaryon / response to oxidative stress / microtubule / early endosome / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / postsynaptic density / ciliary basal body / positive regulation of cell migration / axon / negative regulation of cell population proliferation / negative regulation of gene expression / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / centrosome / positive regulation of gene expression / protein-containing complex binding / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / glutamatergic synapse / endoplasmic reticulum / Golgi apparatus / signal transduction
Similarity search - Function
: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 ...: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
ADENOSINE-5'-DIPHOSPHATE / Chem-M3K / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.6 Å
AuthorsHartung, I.V. / Hitchcock, M. / Puehler, F. / Neuhaus, R. / Scholz, A. / Hammer, S. / Petersen, K. / Siemeister, G. / Brittain, D. / Hillig, R.C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Optimization of Allosteric Mek Inhibitors - Part 1: Venturing Into Unexplored Sar Territories
Authors: Hartung, I.V. / Hitchcock, M. / Puehler, F. / Neuhaus, R. / Scholz, A. / Hammer, S. / Petersen, K. / Siemeister, G. / Brittain, D. / Hillig, R.C.
History
DepositionApr 24, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2013Group: Database references
Revision 1.2Apr 17, 2013Group: Database references
Revision 1.3Dec 14, 2016Group: Data collection
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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_conn.ptnr2_label_seq_id / _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: DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8604
Polymers37,9311
Non-polymers9303
Water86548
1
A: DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1
hetero molecules

A: DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,7218
Polymers75,8612
Non-polymers1,8596
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_665-x+1,-y+1,z1
Buried area3750 Å2
ΔGint-47.2 kcal/mol
Surface area26410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.411, 82.411, 130.238
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number171
Space group name H-MP62

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Components

#1: Protein DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1 / MAP KINASE KINASE 1 / MAPKK 1 / MKK1 / ERK ACTIVATOR KINASE 1 / MAPK/ERK KINASE 1 / MEK 1


Mass: 37930.609 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 62-393
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PQE80L / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): ARCTIC EXPRESS
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, 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-M3K / 2-([3R-3,4-dihydroxybutyl]oxy)-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]benzamide


Mass: 478.229 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17F2IN2O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 48 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsN-TERMINAL M IS CLONING ARTIFACT. LAST EIGHT C-TERMINAL RESIDUES ARE A CLONING ARTIFACT, HEXA HIS ...N-TERMINAL M IS CLONING ARTIFACT. LAST EIGHT C-TERMINAL RESIDUES ARE A CLONING ARTIFACT, HEXA HIS TAG. THIS C- TERMINAL HIS TAG WAS NOT REMOVED BEFORE CRYSTALLIZATION.

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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: 3.55 Å3/Da / Density % sol: 65.34 % / Description: NONE
Crystal growDetails: 0.1 M IMIDAZOLE-MALATE, 300 MM(NH4)H2PO4, 13% PEG 8000, PH 5.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.979
DetectorType: ADSC CCD / Detector: CCD / Date: Jul 24, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.6→30 Å / Num. obs: 15320 / % possible obs: 99.1 % / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 87.17 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 11.9
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 1.7 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.4.0062refinement
MOSFLMdata reduction
SCALAdata scaling
REFMAC5phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PROTEIN CHAIN OF PDB ENTRY 1S9J

1s9j


Resolution: 2.6→19.8 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.951 / SU B: 16.819 / SU ML: 0.191 / Cross valid method: THROUGHOUT / ESU R: 0.317 / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. LIGAND (M3K) CO-CRYSTALLIZED IN THE PRESENCE OF MG AND ADP AS PUBLISHED FOR THE ATP COMPLEX DESCRIBED IN PDB ENTRY 1S9J.
RfactorNum. reflection% reflectionSelection details
Rfree0.21135 769 5 %RANDOM
Rwork0.17205 ---
obs0.17395 14461 98.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 91.152 Å2
Baniso -1Baniso -2Baniso -3
1-1.53 Å20.76 Å20 Å2
2--1.53 Å20 Å2
3----2.29 Å2
Refinement stepCycle: LAST / Resolution: 2.6→19.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2279 0 54 48 2381
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222382
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4372.0053216
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7355289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.32324.44499
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.10515428
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.6351512
X-RAY DIFFRACTIONr_chiral_restr0.10.2351
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211757
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.69421446
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.94332334
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.782936
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.863882
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.6→2.66 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.334 59 -
Rwork0.336 1017 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.76372.0090.89327.83932.207910.39190.1477-0.43320.1766-0.0217-0.22230.76690.489-1.13990.0746-0.3319-0.1175-0.03860.2258-0.0577-0.410930.9452751.437
24.55490.13491.16733.05950.39746.13230.09480.07420.6308-0.3209-0.1516-0.4678-0.37760.20530.0568-0.41960.08250.0989-0.0984-0.0222-0.326740.31736.8628.816
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A61 - 119
2X-RAY DIFFRACTION1A128 - 145
3X-RAY DIFFRACTION2A120 - 127
4X-RAY DIFFRACTION2A146 - 382

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