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- PDB-4u7z: Mitogen-Activated Protein Kinase Kinase (MEK1) bound to G805 -

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Basic information

Entry
Database: PDB / ID: 4u7z
TitleMitogen-Activated Protein Kinase Kinase (MEK1) bound to G805
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / Kinase / inhibitor / Complex / 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 / labyrinthine layer development / type B pancreatic cell proliferation / 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 / labyrinthine layer development / type B pancreatic cell proliferation / MAP-kinase scaffold activity / cerebellar cortex formation / Signaling by MAP2K mutants / regulation of Golgi inheritance / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / regulation of stress-activated MAPK cascade / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / protein kinase activator activity / endodermal cell differentiation / face development / 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 / neuron differentiation / positive regulation of protein serine/threonine kinase activity / 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 / early endosome / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / negative regulation of cell population proliferation / protein phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / centrosome / 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
Chem-3EW / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.805 Å
AuthorsRobarge, K.D. / Ultsch, M.H. / Wiesmann, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2014
Title: Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479.
Authors: Robarge, K.D. / Lee, W. / Eigenbrot, C. / Ultsch, M. / Wiesmann, C. / Heald, R. / Price, S. / Hewitt, J. / Jackson, P. / Savy, P. / Burton, B. / Choo, E.F. / Pang, J. / Boggs, J. / Yang, A. ...Authors: Robarge, K.D. / Lee, W. / Eigenbrot, C. / Ultsch, M. / Wiesmann, C. / Heald, R. / Price, S. / Hewitt, J. / Jackson, P. / Savy, P. / Burton, B. / Choo, E.F. / Pang, J. / Boggs, J. / Yang, A. / Yang, X. / Baumgardner, M.
History
DepositionJul 31, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 24, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2014Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_assembly / pdbx_struct_conn_angle / pdbx_struct_oper_list / refine_hist / struct_conn / struct_keywords
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _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.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.value / _pdbx_struct_oper_list.symmetry_operation / _struct_conn.pdbx_dist_value / _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_keywords.text

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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)38,9184
Polymers37,9301
Non-polymers9883
Water19811
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.845, 81.845, 129.604
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 / MKK1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK 1


Mass: 37929.625 Da / Num. of mol.: 1 / Fragment: kinase domain (UNP residues 62-393)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Plasmid: pET24B / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2 PLysS
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-3EW / 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide / Selumetinib


Mass: 457.681 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15BrClFN4O3 / Comment: medication*YM
#4: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 3.3 Å3/Da / Density % sol: 62.77 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.9
Details: The protein was concentrated to 15mg/ml and incubated with 10 fold molar excess inhibitor plus 1mM MgAMP-PNP before crystallization. MEK1 crystals grew from hanging drop vapor diffusion ...Details: The protein was concentrated to 15mg/ml and incubated with 10 fold molar excess inhibitor plus 1mM MgAMP-PNP before crystallization. MEK1 crystals grew from hanging drop vapor diffusion using 12% w/v PEG 8000, 0.4M NH4H2PO4 and 0.1M HEPES pH 6.9 at 18 degC.
PH range: 6.9

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 6, 2006
RadiationMonochromator: Side scattering bent cube-root I-beam single crystal; asymmetric cut 4.965 degs
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. all: 12041 / Num. obs: 12041 / % possible obs: 80.6 % / Observed criterion σ(I): 2 / Redundancy: 1.8 % / Biso Wilson estimate: 76.3 Å2 / Rsym value: 0.08 / Net I/σ(I): 17.9
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.588 / Mean I/σ(I) obs: 1.2 / % possible all: 88.6

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Processing

SoftwareName: PHENIX / Version: (phenix.refine: 1.8.2_1309) / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1S9J

1s9j


Resolution: 2.805→19.659 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.39 / Phase error: 23.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2144 586 4.87 %Random Selection
Rwork0.1609 ---
obs0.1634 12037 99.84 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.805→19.659 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2275 0 59 11 2345
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092383
X-RAY DIFFRACTIONf_angle_d1.253220
X-RAY DIFFRACTIONf_dihedral_angle_d15.351895
X-RAY DIFFRACTIONf_chiral_restr0.077352
X-RAY DIFFRACTIONf_plane_restr0.005407
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.805-3.08640.31241580.24352838X-RAY DIFFRACTION100
3.0864-3.53080.27011440.20722859X-RAY DIFFRACTION100
3.5308-4.440.21571440.15022859X-RAY DIFFRACTION100
4.44-5.90.17281400.13792895X-RAY DIFFRACTION100
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)
17.51580.3471-4.83985.80480.52278.3177-0.1483-0.35350.62270.26690.2483-0.2666-0.78671.2451-0.10830.7209-0.1398-0.17120.63920.07290.473-29.040226.615729.944
24.2084-0.7431-0.82873.07660.89895.4071-0.1993-0.2458-0.10440.40260.0166-0.1343-0.225-0.06340.1730.5853-0.0826-0.0390.32310.10560.4331-34.017823.116815.7154
31.3362-0.2022-2.5332.03-0.2844.9992-0.15150.35360.07870.30860.02980.0855-0.72490.0941-0.01760.8641-0.1651-0.12240.56790.01950.5584-30.939132.48994.0692
43.4012-0.56820.46664.6426-1.31124.4293-0.09570.3196-0.8277-0.2082-0.1291-0.39960.51320.20970.2220.6536-0.09510.09640.4121-0.10890.6385-26.327814.68-2.0425
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 61 through 91 )
2X-RAY DIFFRACTION2chain 'A' and (resid 92 through 206 )
3X-RAY DIFFRACTION3chain 'A' and (resid 207 through 241 )
4X-RAY DIFFRACTION4chain 'A' and (resid 242 through 382 )

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