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- PDB-4anb: Crystal structures of human MEK1 with carboxamide-based allosteri... -

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Entry
Database: PDB / ID: 4anb
TitleCrystal structures of human MEK1 with carboxamide-based allosteric inhibitor XL518 (GDC-0973), or related analogs.
ComponentsDUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1
KeywordsTRANSFERASE / MAP2K1 / ATP-BINDING / ALLOSTERIC INHIBITION
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
PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / Chem-YQY / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsRice, K.D. / Aay, N. / Anand, N.K. / Blazey, C.M. / Bowles, O.J. / Bussenius, J. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. ...Rice, K.D. / Aay, N. / Anand, N.K. / Blazey, C.M. / Bowles, O.J. / Bussenius, J. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. / Engst, S. / Joshi, A.A. / Kennedy, A.R. / Kim, A.I. / Koltun, E.S. / Lougheed, J.C. / Manalo, J.C.L. / Martini, J.F. / Nuss, J.M. / Peto, C.J. / Tsang, T.H. / Yu, P. / Johnston, S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2012
Title: Novel Carboxamide-Based Allosteric Mek Inhibitors: Discovery and Optimization Efforts Toward Xl518 (Gdc-0973)
Authors: Rice, K.D. / Aay, N. / Anand, N.K. / Blazey, C.M. / Bowles, O.J. / Bussenius, J. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. / Engst, S. / Joshi, A.A. / Kennedy, A.R. / Kim, A. ...Authors: Rice, K.D. / Aay, N. / Anand, N.K. / Blazey, C.M. / Bowles, O.J. / Bussenius, J. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. / Engst, S. / Joshi, A.A. / Kennedy, A.R. / Kim, A.I. / Koltun, E.S. / Lougheed, J.C. / Manalo, J.C.L. / Martini, J.F. / Nuss, J.M. / Peto, C.J. / Tsang, T.H. / Yu, P. / Johnston, S.
History
DepositionMar 16, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 19, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2014Group: Database references
Revision 2.0Jun 20, 2018Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations
Category: atom_site / pdbx_nonpoly_scheme ...atom_site / pdbx_nonpoly_scheme / pdbx_struct_conn_angle / pdbx_struct_sheet_hbond / pdbx_validate_close_contact / pdbx_validate_symm_contact / struct_conf / struct_conn / struct_conn_type / struct_sheet / struct_sheet_order / struct_sheet_range / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_seq_id / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_nonpoly_scheme.pdb_seq_num / _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_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 / _pdbx_struct_sheet_hbond.range_1_auth_comp_id / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_comp_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_comp_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_comp_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_struct_sheet_hbond.sheet_id / _pdbx_validate_close_contact.auth_atom_id_1 / _pdbx_validate_close_contact.auth_atom_id_2 / _pdbx_validate_close_contact.auth_comp_id_1 / _pdbx_validate_close_contact.auth_comp_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _pdbx_validate_close_contact.dist / _pdbx_validate_symm_contact.auth_seq_id_1 / _pdbx_validate_symm_contact.auth_seq_id_2 / _pdbx_validate_symm_contact.dist / _struct_conf.pdbx_PDB_helix_id / _struct_sheet.id / _struct_sheet_order.sheet_id / _struct_sheet_range.sheet_id / _struct_site.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id / _struct_site_gen.auth_seq_id
Revision 2.1May 8, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 2.2May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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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)34,6214
Polymers33,6151
Non-polymers1,0073
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)109.001, 109.001, 48.076
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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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: 33614.730 Da / Num. of mol.: 1 / Fragment: PROTEIN KINASE DOMAIN, RESIDUES 61-262,305-392 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: Q02750, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-YQY / [3-(AMINOMETHYL)-3-OXIDANYL-AZETIDIN-1-YL]-[3,4-BIS(FLUORANYL)-2-[(2-FLUORANYL-4-IODANYL-PHENYL)AMINO]PHENYL]METHANONE


Mass: 477.220 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15F3IN3O2
#3: Chemical ChemComp-ACP / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / ADENOSINE-5'-[BETA, GAMMA-METHYLENE]TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 1 / 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.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 57 / 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: 2.32 Å3/Da / Density % sol: 47 % / Description: NONE
Crystal growMethod: vapor diffusion, sitting drop / pH: 8.9
Details: SITTING DROP VAPOR DIFFUSION VS. 26.5 % PEG-2000 MME, 0.1 M TRIMETHYLAMINE N-OXIDE, 0.1 M TRIS (PH 8.9)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 10, 2005 / Details: MIRRORS
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→94.49 Å / Num. obs: 16691 / % possible obs: 99.6 % / Observed criterion σ(I): 2 / Redundancy: 5.3 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 14.7
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.82 / Mean I/σ(I) obs: 2 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: UNPUBLISHED MEK1-ATP STRUCTURE

Resolution: 2.2→94.49 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.909 / SU B: 8.866 / SU ML: 0.225 / Cross valid method: THROUGHOUT / ESU R: 0.303 / ESU R Free: 0.254 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.29585 858 5.1 %RANDOM
Rwork0.22622 ---
obs0.22982 15814 99.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 59.44 Å2
Baniso -1Baniso -2Baniso -3
1--2.21 Å2-1.1 Å20 Å2
2---2.21 Å20 Å2
3---3.31 Å2
Refinement stepCycle: LAST / Resolution: 2.2→94.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2209 0 58 57 2324
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0222314
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.1252.0093129
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0245280
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.58824.22797
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.53715415
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.8091513
X-RAY DIFFRACTIONr_chiral_restr0.1290.2340
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021709
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2380.21124
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3140.21552
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2270.2112
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.0530.21
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3060.222
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.4240.211
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0591.51415
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.77422255
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.7243995
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.8994.5872
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.258 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.403 64 -
Rwork0.284 1157 -
obs--99.92 %

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