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- PDB-3sls: Crystal Structure of human MEK-1 kinase in complex with UCB135377... -

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Basic information

Entry
Database: PDB / ID: 3sls
TitleCrystal Structure of human MEK-1 kinase in complex with UCB1353770 and AMPPNP
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Serine-threonine kinase / Signalling / 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 / 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 / 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-77D / 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: 2.3 Å
AuthorsMeier, C. / Ceska, T.A.
Citation
Journal: J.Struct.Biol. / Year: 2012
Title: Engineering human MEK-1 for structural studies: A case study of combinatorial domain hunting.
Authors: Meier, C. / Brookings, D.C. / Ceska, T.A. / Doyle, C. / Gong, H. / McMillan, D. / Saville, G.P. / Mushtaq, A. / Knight, D. / Reich, S. / Pearl, L.H. / Powell, K.A. / Savva, R. / Allen, R.A.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Fused thiophene derivatives as MEK inhibitors.
Authors: Laing, V.E. / Brookings, D.C. / Carbery, R.J. / Simorte, J.G. / Hutchings, M.C. / Langham, B.J. / Lowe, M.A. / Allen, R.A. / Fetterman, J.R. / Turner, J. / Meier, C. / Kennedy, J. / Merriman, M.
History
DepositionJun 25, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 29, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ncs_dom_lim / 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_asym_id / _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_asym_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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_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: Dual specificity mitogen-activated protein kinase kinase 1
B: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,9608
Polymers67,7862
Non-polymers2,1746
Water6,485360
1
A: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9804
Polymers33,8931
Non-polymers1,0873
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9804
Polymers33,8931
Non-polymers1,0873
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.502, 153.890, 48.209
Angle α, β, γ (deg.)90.00, 101.48, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDRefine codeAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11METMETGLUGLU5AA42 - 1021 - 61
21METMETGLUGLU5BB42 - 1021 - 61
12ALAALASERSER3AA106 - 21265 - 171
22ALAALASERSER3BB106 - 21265 - 171
13SERSERGLNGLN2AA228 - 236187 - 195
23SERSERGLNGLN2BB228 - 236187 - 195
14GLNGLNILEILE3AA243 - 263202 - 222
24GLNGLNILEILE3BB243 - 263202 - 222
15GLUGLUHOHHOH3AA - I310 - 376269
25GLUGLUHOHHOH3BB - J310 - 376269
16HOHHOHHOHHOH5AI377 - 382
26HOHHOHHOHHOH5BJ377 - 382

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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: 33893.227 Da / Num. of mol.: 2 / Fragment: MEK-1 F11 fragment / Mutation: delta 264-307
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: Human MEK-1 kinase, MAP2K1, MEK1, PRKMK1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-77D / 2-[(2-fluoro-4-iodophenyl)amino]-5,5-dimethyl-8-oxo-N-[(3R)-piperidin-3-yl]-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine-3-carboxamide


Mass: 556.435 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H26FIN4O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 360 / 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: 2.55 Å3/Da / Density % sol: 51.72 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 18% PEG-3350, 200mM Ammonium fluoride, 4% Glycerol, 10mM DTT, VAPOR DIFFUSION, SITTING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX14.2
DetectorType: CUSTOM-MADE / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.3→30.29 Å / Num. obs: 30851

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Processing

Software
NameVersionClassification
PHASERphasing
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→30 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.892 / SU B: 8.965 / SU ML: 0.22 / Cross valid method: THROUGHOUT / ESU R Free: 0.283 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28654 1508 5.1 %RANDOM
Rwork0.20574 ---
obs0.20975 28304 99.26 %-
all-29851 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.581 Å2
Baniso -1Baniso -2Baniso -3
1-1.49 Å20 Å21.48 Å2
2--0.21 Å20 Å2
3----1.11 Å2
Refinement stepCycle: LAST / Resolution: 2.3→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4526 0 126 360 5012
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0224762
X-RAY DIFFRACTIONr_angle_refined_deg1.2872.0076439
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6855587
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.28224.394198
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.48715843
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.51526
X-RAY DIFFRACTIONr_chiral_restr0.0840.2704
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023564
X-RAY DIFFRACTIONr_nbd_refined0.1990.22297
X-RAY DIFFRACTIONr_nbtor_refined0.2960.23250
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1740.2318
X-RAY DIFFRACTIONr_metal_ion_refined0.090.23
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1930.241
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2920.212
X-RAY DIFFRACTIONr_mcbond_it0.5731.52924
X-RAY DIFFRACTIONr_mcangle_it1.01824659
X-RAY DIFFRACTIONr_scbond_it1.17732008
X-RAY DIFFRACTIONr_scangle_it1.8234.51776
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
691tight positional0.040.05
283medium positional0.270.5
816loose positional0.65
691tight thermal0.080.5
283medium thermal0.392
816loose thermal0.8710
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.381 108 -
Rwork0.301 2055 -
obs--98.59 %

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