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- PDB-4mne: Crystal structure of the BRAF:MEK1 complex -

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Basic information

Entry
Database: PDB / ID: 4mne
TitleCrystal structure of the BRAF:MEK1 complex
Components
  • Dual specificity mitogen-activated protein kinase kinase 1
  • Serine/threonine-protein kinase B-raf
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / RAF / MAPK / kinase domain / ATP-binding / ERK / RAS / PAK / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / regulation of axon regeneration / mitogen-activated protein kinase kinase / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / trehalose metabolism in response to stress / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / regulation of axon regeneration / mitogen-activated protein kinase kinase / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / type B pancreatic cell proliferation / head morphogenesis / MAP-kinase scaffold activity / Signalling to p38 via RIT and RIN / cerebellar cortex formation / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Signaling by MAP2K mutants / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / regulation of Golgi inheritance / mitogen-activated protein kinase kinase binding / trachea formation / regulation of T cell differentiation / 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 / stress fiber assembly / protein kinase activator activity / positive regulation of axon regeneration / endodermal cell differentiation / face development / MAPK3 (ERK1) activation / synaptic vesicle exocytosis / somatic stem cell population maintenance / Bergmann glial cell differentiation / MAP kinase kinase activity / thyroid gland development / Uptake and function of anthrax toxins / MAP kinase kinase kinase activity / Schwann cell development / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / keratinocyte differentiation / positive regulation of stress fiber assembly / response to cAMP / cellular response to calcium ion / ERK1 and ERK2 cascade / myelination / protein serine/threonine/tyrosine kinase activity / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / substrate adhesion-dependent cell spreading / insulin-like growth factor receptor signaling pathway / cellular response to nerve growth factor stimulus / thymus development / Signal transduction by L1 / cell motility / long-term synaptic potentiation / animal organ morphogenesis / Spry regulation of FGF signaling / RAF activation / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / neuron differentiation / positive regulation of protein serine/threonine kinase activity / epidermal growth factor receptor signaling pathway / response to peptide hormone / Negative regulation of MAPK pathway / 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 / cellular response to xenobiotic stimulus / late endosome / presynapse / positive regulation of peptidyl-serine phosphorylation / heart development / T cell differentiation in thymus / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / scaffold protein binding / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / Ras protein signal transduction / early endosome / positive regulation of ERK1 and ERK2 cascade
Similarity search - Function
Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain ...Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / 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-573 / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / Serine/threonine-protein kinase B-raf / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8483 Å
AuthorsSudhamsu, J. / Haling, J.R. / Morales, T. / Brandhuber, B. / Hymowitz, S.G.
CitationJournal: Cancer Cell / Year: 2014
Title: Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling.
Authors: Haling, J.R. / Sudhamsu, J. / Yen, I. / Sideris, S. / Sandoval, W. / Phung, W. / Bravo, B.J. / Giannetti, A.M. / Peck, A. / Masselot, A. / Morales, T. / Smith, D. / Brandhuber, B.J. / Hymowitz, S.G. / Malek, S.
History
DepositionSep 10, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 18, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 3, 2014Group: Database references
Revision 1.2Sep 24, 2014Group: Database references
Revision 1.3Sep 20, 2023Group: 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_initial_refinement_model / 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_asym_id / _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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_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_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
B: Serine/threonine-protein kinase B-raf
C: Serine/threonine-protein kinase B-raf
D: Dual specificity mitogen-activated protein kinase kinase 1
E: Dual specificity mitogen-activated protein kinase kinase 1
F: Serine/threonine-protein kinase B-raf
G: Serine/threonine-protein kinase B-raf
H: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)297,70922
Polymers293,1108
Non-polymers4,60014
Water2,180121
1
A: Dual specificity mitogen-activated protein kinase kinase 1
B: Serine/threonine-protein kinase B-raf
C: Serine/threonine-protein kinase B-raf
D: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,59210
Polymers146,5554
Non-polymers2,0376
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
E: Dual specificity mitogen-activated protein kinase kinase 1
F: Serine/threonine-protein kinase B-raf
G: Serine/threonine-protein kinase B-raf
H: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,11712
Polymers146,5554
Non-polymers2,5628
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)97.498, 135.657, 256.059
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 8 molecules ADEHBCFG

#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.: 4 / Fragment: 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 DE3
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Protein
Serine/threonine-protein kinase B-raf / BRAF / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 35346.812 Da / Num. of mol.: 4 / Fragment: kinase domain (UNP residues 432-726)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P15056, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 135 molecules

#3: Chemical
ChemComp-ACP / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / ADENOSINE-5'-[BETA, GAMMA-METHYLENE]TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Comment: AMP-PCP, energy-carrying molecule analogue*YM
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Chemical
ChemComp-573 / 7-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-N-{[(2S)-2-hydroxypropyl]oxy}furo[3,2-c]pyridine-2-carboxamide


Mass: 489.212 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C17H14F2IN3O4
#6: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 2.89 Å3/Da / Density % sol: 57.42 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 20% PEG8000, 0.1 M Tris, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 24, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.8483→39.59 Å / Num. all: 79897 / Num. obs: 79897 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.7 % / Rsym value: 0.113 / Net I/σ(I): 13.5
Reflection shellResolution: 2.8483→3 Å / Redundancy: 6.9 % / Mean I/σ(I) obs: 2.8 / Rsym value: 0.721 / % possible all: 98.5

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
autoXDSdata reduction
autoXDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRIES 3PP1 AND 3Q4C

3pp1

3q4c


Resolution: 2.8483→39.586 Å / SU ML: 0.4 / σ(F): 1.34 / σ(I): 2.8 / Phase error: 25.88 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2402 1999 2.5 %RANDOM
Rwork0.185 ---
obs0.1864 79897 99.64 %-
all-79897 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.8483→39.586 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17251 0 264 121 17636
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00917968
X-RAY DIFFRACTIONf_angle_d1.26424312
X-RAY DIFFRACTIONf_dihedral_angle_d15.6856777
X-RAY DIFFRACTIONf_chiral_restr0.0812667
X-RAY DIFFRACTIONf_plane_restr0.0053072
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8483-2.91950.35961370.28475317X-RAY DIFFRACTION97
2.9195-2.99840.37611410.25355503X-RAY DIFFRACTION100
2.9984-3.08660.28751420.23825558X-RAY DIFFRACTION100
3.0866-3.18620.3141410.22935498X-RAY DIFFRACTION100
3.1862-3.30010.31731420.23265524X-RAY DIFFRACTION100
3.3001-3.43210.30561410.21315529X-RAY DIFFRACTION100
3.4321-3.58820.28461420.20095530X-RAY DIFFRACTION100
3.5882-3.77730.23511430.17915565X-RAY DIFFRACTION100
3.7773-4.01370.251430.17555557X-RAY DIFFRACTION100
4.0137-4.32330.19321420.1475543X-RAY DIFFRACTION100
4.3233-4.75770.20091440.1415604X-RAY DIFFRACTION100
4.7577-5.44460.20281440.15485635X-RAY DIFFRACTION100
5.4446-6.85380.21231470.1895665X-RAY DIFFRACTION100
6.8538-39.58950.2031500.18065870X-RAY DIFFRACTION99

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