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- PDB-8pas: Crystal structure of MAP4K1 with a SMOL inhibitor -

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Basic information

Entry
Database: PDB / ID: 8pas
TitleCrystal structure of MAP4K1 with a SMOL inhibitor
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / kinase / inhibitor / drug discovery
Function / homology
Function and homology information


MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / cell population proliferation / positive regulation of MAPK cascade / protein autophosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / cell population proliferation / positive regulation of MAPK cascade / protein autophosphorylation / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / ATP binding / membrane / cytoplasm
Similarity search - Function
Mitogen-activated protein (MAP) kinase kinase kinase kinase / Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / CNH domain / Citron homology (CNH) domain / Citron homology (CNH) domain profile. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. ...Mitogen-activated protein (MAP) kinase kinase kinase kinase / Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2 / CNH domain / Citron homology (CNH) domain / Citron homology (CNH) domain profile. / 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
Similarity search - Domain/homology
: / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsFriberg, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Identification and optimization of Azaindole based MAP4K1 Inhibitors and the discovery of BAY-405
Authors: Mowat, J. / Carretero, R. / Leder, G. / Aiguabella Font, N. / Neuhaus, R. / Berndt, S. / Guenther, J. / Friberg, A. / Schaefer, M. / Briem, H. / Raschke, M. / Miyatake Ondozabal, H. / ...Authors: Mowat, J. / Carretero, R. / Leder, G. / Aiguabella Font, N. / Neuhaus, R. / Berndt, S. / Guenther, J. / Friberg, A. / Schaefer, M. / Briem, H. / Raschke, M. / Miyatake Ondozabal, H. / Buchmann, B. / Boemer, U. / Hartung, I. / Offringa, R.
History
DepositionJun 8, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase kinase kinase kinase 1
B: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,8664
Polymers64,7252
Non-polymers1,1412
Water00
1
A: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9332
Polymers32,3631
Non-polymers5711
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9332
Polymers32,3631
Non-polymers5711
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.040, 100.056, 61.055
Angle α, β, γ (deg.)90.00, 102.03, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Mitogen-activated protein kinase kinase kinase kinase 1 / Hematopoietic progenitor kinase / MAPK/ERK kinase kinase kinase 1 / MEK kinase kinase 1 / MEKKK 1


Mass: 32362.666 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP4K1, HPK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q92918, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-XOH / 4-[2,6-bis(fluoranyl)-4-(3-morpholin-4-ylpropylcarbamoylamino)phenoxy]-~{N}-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1~{H}-pyrrolo[2,3-b]pyridine-3-carboxamide


Mass: 570.548 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28F2N8O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.82 Å3/Da / Density % sol: 56.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: NOT DISCLOSED

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99998 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99998 Å / Relative weight: 1
ReflectionResolution: 2.7→42.91 Å / Num. obs: 19051 / % possible obs: 96.1 % / Redundancy: 3 % / CC1/2: 0.999 / Rrim(I) all: 0.049 / Rsym value: 0.041 / Net I/σ(I): 21.55
Reflection shellResolution: 2.7→2.95 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 3.5 / Num. unique obs: 4477 / CC1/2: 0.936 / Rrim(I) all: 0.529 / Rsym value: 0.439 / % possible all: 97

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→42.91 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.895 / SU B: 45.126 / SU ML: 0.399 / Cross valid method: THROUGHOUT / ESU R: 1.494 / ESU R Free: 0.407 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2997 811 4.3 %RANDOM
Rwork0.22808 ---
obs0.23093 18239 96.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 81.876 Å2
Baniso -1Baniso -2Baniso -3
1-1.03 Å20 Å21.35 Å2
2---4.57 Å2-0 Å2
3---2.72 Å2
Refinement stepCycle: 1 / Resolution: 2.7→42.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4282 0 82 0 4364
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0134461
X-RAY DIFFRACTIONr_bond_other_d0.0030.0164370
X-RAY DIFFRACTIONr_angle_refined_deg1.8871.6586027
X-RAY DIFFRACTIONr_angle_other_deg1.3821.60910077
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.3735535
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.02922.427206
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.62215800
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.3731524
X-RAY DIFFRACTIONr_chiral_restr0.0790.2555
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024895
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02973
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.8984.6382161
X-RAY DIFFRACTIONr_mcbond_other2.8984.6372160
X-RAY DIFFRACTIONr_mcangle_it4.6876.9462689
X-RAY DIFFRACTIONr_mcangle_other4.6876.9482690
X-RAY DIFFRACTIONr_scbond_it2.8534.9692300
X-RAY DIFFRACTIONr_scbond_other2.8524.9692301
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.6827.3143339
X-RAY DIFFRACTIONr_long_range_B_refined6.88553.0744879
X-RAY DIFFRACTIONr_long_range_B_other6.88453.0834878
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 7907 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.11 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.702→2.772 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 67 -
Rwork0.355 1361 -
obs--97.61 %
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)
11.9180.63850.53675.08060.31822.15990.0602-0.03320.79360.0475-0.07740.8752-0.3986-0.12120.01710.74950.0682-0.31210.33440.00490.8109-33.90625.1982-26.9797
22.91592.67992.554210.51385.53523.52350.02540.26080.03930.01850.0785-0.15690.12950.1212-0.10390.4935-0.1528-0.27990.21970.05040.179-10.195212.8108-20.434
32.34930.29310.77734.87270.30612.4097-0.0454-0.0309-0.0367-0.2979-0.0173-0.3523-0.03710.05590.06270.4474-0.006-0.25450.00550.00760.2072-14.9146-14.1901-26.8714
42.44661.40940.38735.81860.5662.6182-0.1627-0.3378-0.56991.0079-0.10370.0520.83330.06440.26641.00970.0159-0.19250.31210.09070.5558-4.61997.71369.3993
54.05045.27382.74667.44493.51861.87880.0397-0.3762-0.133-0.2868-0.1027-0.4535-0.0635-0.30470.0630.7277-0.0149-0.3870.2982-0.21010.6573-6.61890.6276-13.7059
62.4570.03390.83074.97240.13442.91260.06150.0757-0.0003-0.3492-0.0153-0.3417-0.03490.004-0.04620.33070.0067-0.24830.0028-0.00170.2695-0.950527.1655-9.7091
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 93
2X-RAY DIFFRACTION2A156 - 191
3X-RAY DIFFRACTION3A94 - 155
4X-RAY DIFFRACTION3A192 - 999
5X-RAY DIFFRACTION4B1 - 93
6X-RAY DIFFRACTION5B156 - 191
7X-RAY DIFFRACTION6B94 - 155
8X-RAY DIFFRACTION6B192 - 999

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