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- PDB-4lmn: Crystal Structure of MEK1 kinase bound to GDC0973 -

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Basic information

Entry
Database: PDB / ID: 4lmn
TitleCrystal Structure of MEK1 kinase bound to GDC0973
ComponentsDual specificity mitogen-activated protein kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Phosphorylation / Braf / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / JUN kinase kinase activity / regulation of axon regeneration / mitogen-activated protein kinase kinase / placenta blood vessel development / MAP-kinase scaffold activity / labyrinthine layer development / cerebellar cortex formation / type B pancreatic cell proliferation ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / JUN kinase kinase activity / regulation of axon regeneration / mitogen-activated protein kinase kinase / placenta blood vessel development / MAP-kinase scaffold activity / labyrinthine layer development / cerebellar cortex formation / type B pancreatic cell proliferation / Signaling by MAP2K mutants / positive regulation of axonogenesis / regulation of Golgi inheritance / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / MAPK3 (ERK1) activation / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / endodermal cell differentiation / face development / MAP kinase kinase activity / 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 / Schwann cell development / keratinocyte differentiation / myelination / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / insulin-like growth factor receptor signaling pathway / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / thymus development / Signal transduction by L1 / cell motility / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / neuron differentiation / chemotaxis / 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 / cellular senescence / Signaling by BRAF and RAF1 fusions / MAPK cascade / late endosome / heart development / protein tyrosine kinase activity / scaffold protein binding / early endosome / positive regulation of ERK1 and ERK2 cascade / protein kinase activity / ciliary basal body / negative regulation of cell population proliferation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / centrosome / positive regulation of gene expression / positive regulation of DNA-templated transcription / endoplasmic reticulum / Golgi apparatus / signal transduction / mitochondrion / ATP binding / nucleus / plasma membrane / cytosol
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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Chem-EUI / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsUltsch, M.H.
CitationJournal: Nature / Year: 2013
Title: Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers.
Authors: Hatzivassiliou, G. / Haling, J.R. / Chen, H. / Song, K. / Price, S. / Heald, R. / Hewitt, J.F. / Zak, M. / Peck, A. / Orr, C. / Merchant, M. / Hoeflich, K.P. / Chan, J. / Luoh, S.M. / ...Authors: Hatzivassiliou, G. / Haling, J.R. / Chen, H. / Song, K. / Price, S. / Heald, R. / Hewitt, J.F. / Zak, M. / Peck, A. / Orr, C. / Merchant, M. / Hoeflich, K.P. / Chan, J. / Luoh, S.M. / Anderson, D.J. / Ludlam, M.J. / Wiesmann, C. / Ultsch, M. / Friedman, L.S. / Malek, S. / Belvin, M.
History
DepositionJul 10, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2013Group: Database references
Revision 1.2Sep 25, 2013Group: Database references
Revision 1.3Feb 28, 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_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_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_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_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)38,9924
Polymers37,9311
Non-polymers1,0623
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
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)77,9858
Polymers75,8612
Non-polymers2,1246
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_665-x+1,-y+1,z1
Buried area5970 Å2
ΔGint-29 kcal/mol
Surface area25680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.610, 81.610, 129.809
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: Kinase domain (UNP residues 62-393)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: 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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-EUI / [3,4-BIS(FLUORANYL)-2-[(2-FLUORANYL-4-IODANYL-PHENYL)AMINO]PHENYL]-[3-OXIDANYL-3-[(2S)-PIPERIDIN-2-YL]AZETIDIN-1-YL]METHANONE


Mass: 531.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21F3IN3O2 / Comment: medication, anticancer, inhibitor*YM

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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: 3.29 Å3/Da / Density % sol: 62.61 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.9
Details: 12% w/v PEG 8000, 0.4M NH4H2PO4, 0.1M HEPES, pH 6.9, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Mar 14, 2008 / Details: mirrors
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 12090 / % possible obs: 99.9 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 90.68 Å2 / Rsym value: 0.052 / Net I/σ(I): 2.7
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 2.7 / Rsym value: 0.628 / % possible all: 100

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Processing

Software
NameVersionClassification
HKL-2000data collection
AMoREphasing
REFMAC5.2.0005refinement
HKL-2000data reduction
SCALEPACKdata scaling
BUSTER2.11.4refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→29.69 Å / Cor.coef. Fo:Fc: 0.9528 / Cor.coef. Fo:Fc free: 0.9189 / SU B: 32.665 / SU ML: 0.276 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.636 / ESU R Free: 0.33 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2329 587 4.87 %RANDOM
Rwork0.1913 ---
obs0.1932 12053 99.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 87.84 Å2
Baniso -1Baniso -2Baniso -3
1--6.7786 Å20 Å20 Å2
2---6.7786 Å20 Å2
3---13.5572 Å2
Refine analyzeLuzzati coordinate error obs: 0.496 Å
Refinement stepCycle: LAST / Resolution: 2.8→29.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2286 0 62 0 2348
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012404HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.283259HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d850SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes56HARMONIC2
X-RAY DIFFRACTIONt_gen_planes338HARMONIC5
X-RAY DIFFRACTIONt_it2404HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion
X-RAY DIFFRACTIONt_other_torsion
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact
LS refinement shellResolution: 2.8→3.07 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2884 153 5.34 %
Rwork0.2574 2710 -
all0.2591 2863 -
obs--99.69 %
Refinement TLS params.Method: refined / Origin x: 30.1414 Å / Origin y: 21.3598 Å / Origin z: -9.1066 Å
111213212223313233
T-0.0039 Å20.1452 Å2-0.0242 Å2--0.2363 Å2-0.0144 Å2---0.1023 Å2
L2.7695 °2-0.2265 °2-0.855 °2-1.6799 °20.3996 °2--5.2964 °2
S-0.1122 Å °0.0508 Å °-0.5813 Å °-0.0345 Å °-0.0466 Å °0.2093 Å °-0.0538 Å °-0.1945 Å °0.1588 Å °

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