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- PDB-3dv3: MEK1 with PF-04622664 Bound -

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Basic information

Entry
Database: PDB / ID: 3dv3
TitleMEK1 with PF-04622664 Bound
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE / Kinase / Kinase inhibitors / MEK / ATP-binding / Disease mutation / Nucleotide-binding / Phosphoprotein / Serine/threonine-protein kinase / Tyrosine-protein kinase
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 / MAP-kinase scaffold activity / type B pancreatic cell proliferation / 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 / MAP-kinase scaffold activity / type B pancreatic cell proliferation / 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 / protein serine/threonine/tyrosine kinase activity / myelination / 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 / 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
ADENOSINE-5'-TRIPHOSPHATE / Chem-MEK / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.3 Å
AuthorsKazmirski, S.L. / Kothe, M. / Ding, Y.-H.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Beyond the MEK-pocket: can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?
Authors: Tecle, H. / Shao, J. / Li, Y. / Kothe, M. / Kazmirski, S. / Penzotti, J. / Ding, Y.H. / Ohren, J. / Moshinsky, D. / Coli, R. / Jhawar, N. / Bora, E. / Jacques-O'Hagan, S. / Wu, J.
History
DepositionJul 18, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 21, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
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.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 / _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_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)36,9615
Polymers35,8111
Non-polymers1,1504
Water1,54986
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)73,92210
Polymers71,6232
Non-polymers2,3008
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_655-x+1,-y,z1
Buried area4130 Å2
ΔGint-37 kcal/mol
Surface area25940 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)81.596, 81.596, 129.966
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number171
Space group name H-MP62
Components on special symmetry positions
IDModelComponents
11A-9056-

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 / MEK1


Mass: 35811.348 Da / Num. of mol.: 1 / Fragment: UNP residues 62-382
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q02750, mitogen-activated protein kinase kinase

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Non-polymers , 5 types, 90 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#4: Chemical ChemComp-MEK / 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(2-hydroxyethoxy)methyl]benzamide


Mass: 526.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18F3IN2O5
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 3.49 Å3/Da / Density % sol: 64.73 %
Crystal growMethod: vapor diffusion, hanging drop / Details: VAPOR DIFFUSION, HANGING DROP

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM
DetectorType: MAR CCD 165 mm / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.25→100 Å / Num. obs: 23200 / % possible obs: 99.2 % / Redundancy: 7.6 % / Rmerge(I) obs: 0.049 / Χ2: 1.405 / Net I/σ(I): 12.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.25-2.336.70.77723286.0021100
2.33-2.427.60.35123170.4521100
2.42-2.537.70.24523320.4681100
2.53-2.677.70.16423210.5521100
2.67-2.837.70.12723510.671100
2.83-3.057.80.07223190.6261100
3.05-3.367.80.05223480.8281100
3.36-3.857.70.04423371.3211100
3.85-4.857.60.03723351.691199.6
4.85-1007.30.03822122.214192.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMAC5.2.0019refinement
PDB_EXTRACT3.006data extraction
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→47.83 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.944 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 9.524 / SU ML: 0.133 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.203 / ESU R Free: 0.178 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.221 1103 5.1 %RANDOM
Rwork0.182 ---
obs0.184 21515 99.18 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 80.72 Å2 / Biso mean: 55.39 Å2 / Biso min: 39.39 Å2
Baniso -1Baniso -2Baniso -3
1-0.55 Å20.28 Å20 Å2
2--0.55 Å20 Å2
3----0.83 Å2
Refinement stepCycle: LAST / Resolution: 2.3→47.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2255 0 67 86 2408
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.0222368
X-RAY DIFFRACTIONr_angle_refined_deg1.92.0123194
X-RAY DIFFRACTIONr_dihedral_angle_1_deg10.5685285
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.63824.4998
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.92115425
X-RAY DIFFRACTIONr_dihedral_angle_4_deg25.9471512
X-RAY DIFFRACTIONr_chiral_restr0.1490.2346
X-RAY DIFFRACTIONr_gen_planes_refined0.010.021736
X-RAY DIFFRACTIONr_nbd_refined0.2140.21062
X-RAY DIFFRACTIONr_nbtor_refined0.3040.21587
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.180.2111
X-RAY DIFFRACTIONr_metal_ion_refined0.1230.22
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.190.232
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1220.23
X-RAY DIFFRACTIONr_mcbond_it0.8781.51446
X-RAY DIFFRACTIONr_mcangle_it1.39922306
X-RAY DIFFRACTIONr_scbond_it2.57431023
X-RAY DIFFRACTIONr_scangle_it3.9734.5888
LS refinement shellResolution: 2.3→2.364 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.388 95 -
Rwork0.299 1535 -
all-1630 -
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)
13.27970.81181.08992.7004-1.27695.5902-0.0097-0.18580.42810.3982-0.1250.1869-0.9301-0.43890.13480.14430.1766-0.0704-0.0299-0.0705-0.169839.5507-11.056512.6327
25.5071-0.1528-1.80952.0794-0.12264.7028-0.0066-0.20690.09640.30490.0254-0.2072-0.124-0.2057-0.0188-0.04910.127-0.1168-0.1790.0356-0.181544.7116-16.78614.8743
34.3092-0.3798-1.02383.29290.0964.3567-0.0269-0.0396-0.5051-0.027-0.0765-0.40550.3371-0.01390.1034-0.10370.1052-0.0299-0.27840.0092-0.117248.1884-21.9202-4.6284
413.0931-3.2216-11.695621.9172-14.585124.883-0.24470.34320.8893-0.1853-0.16640.513-1.38940.26370.4111-0.03750.153-0.09620.1915-0.0365-0.155731.6053-9.6393-3.1478
520.90324.76014.15613.66640.822210.8695-0.0488-0.66071.19380.2344-0.5148-0.0857-0.8004-0.35420.5636-0.00650.0922-0.0082-0.1928-0.0062-0.170244.0159-8.0183-14.8472
66.36721.32351.94116.32360.05935.2941-0.09260.41360.4635-0.3569-0.1668-0.6694-0.2130.18410.2594-0.03830.13630.0661-0.1875-0.0118-0.134850.3826-11.5375-16.6306
726.180914.207-6.937950.535911.97097.6203-0.17951.13660.94421.83430.0428-1.7111-1.96591.260.13670.2799-0.0990.08170.65170.11340.697568.3699-5.7344-18.3344
83.9591-2.4140.18634.8776-0.34343.9396-0.0150.52070.2926-0.6616-0.1451-0.98770.06340.35750.1601-0.01530.0540.0939-0.0508-0.0414-0.051451.6611-15.0666-21.2622
92.3865-0.70491.82868.07524.93789.83850.0149-0.6284-0.62770.2179-0.3217-0.95160.23140.57880.3068-0.08870.15860.05190.00580.04620.404863.0207-24.0822-4.8712
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA61 - 1111 - 51
2X-RAY DIFFRACTION2AA112 - 16152 - 101
3X-RAY DIFFRACTION3AA162 - 212102 - 152
4X-RAY DIFFRACTION4AA213 - 221153 - 161
5X-RAY DIFFRACTION5AA225 - 235165 - 175
6X-RAY DIFFRACTION6AA236 - 269176 - 209
7X-RAY DIFFRACTION7AA270 - 275210 - 215
8X-RAY DIFFRACTION8AA307 - 357247 - 297
9X-RAY DIFFRACTION9AA358 - 382298 - 322

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