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

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Basic information

Entry
Database: PDB / ID: 8pau
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 / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / cell population proliferation / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / 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. ...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: 2.8 Å
AuthorsFriberg, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer.
Authors: Mowat, J. / Carretero, R. / Leder, G. / Aiguabella Font, N. / Neuhaus, R. / Berndt, S. / Gunther, J. / Friberg, A. / Schafer, M. / Briem, H. / Raschke, M. / Miyatake Ondozabal, H. / ...Authors: Mowat, J. / Carretero, R. / Leder, G. / Aiguabella Font, N. / Neuhaus, R. / Berndt, S. / Gunther, J. / Friberg, A. / Schafer, M. / Briem, H. / Raschke, M. / Miyatake Ondozabal, H. / Buchmann, B. / Boemer, U. / Kreft, B. / Hartung, I.V. / Offringa, R.
History
DepositionJun 8, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2025Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)65,5324
Polymers64,6112
Non-polymers9212
Water30617
1
A: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7662
Polymers32,3061
Non-polymers4601
Water181
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)32,7662
Polymers32,3061
Non-polymers4601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)60.983, 99.904, 61.101
Angle α, β, γ (deg.)90.00, 101.94, 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: 32305.615 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-XOR / [(5~{R})-2-[[3,5-bis(fluoranyl)-4-[[3-(trifluoromethyl)-1~{H}-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]amino]-5-fluoranyl-4,6-dihydro-1,3-oxazin-5-yl]methanol


Mass: 460.330 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H14F6N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 56.36 %
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: 0.99984 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99984 Å / Relative weight: 1
ReflectionResolution: 2.8→47.46 Å / Num. obs: 17639 / % possible obs: 99.4 % / Redundancy: 3.3 % / Biso Wilson estimate: 63.8 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.063 / Rsym value: 0.053 / Net I/σ(I): 20.2
Reflection shellResolution: 2.8→3.05 Å / Redundancy: 3.3 % / Mean I/σ(I) obs: 3.99 / Num. unique obs: 3972 / CC1/2: 0.927 / Rrim(I) all: 0.511 / Rsym value: 0.428 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
XSCALEdata scaling
Cootmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→47.46 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.896 / SU B: 51.042 / SU ML: 0.452 / Cross valid method: THROUGHOUT / ESU R Free: 0.399 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2723 794 4.5 %RANDOM
Rwork0.21667 ---
obs0.21928 16844 99.44 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 77.824 Å2
Baniso -1Baniso -2Baniso -3
1-1.96 Å20 Å2-2.13 Å2
2---3.1 Å20 Å2
3---1.88 Å2
Refinement stepCycle: 1 / Resolution: 2.8→47.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4366 0 64 17 4447
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0134532
X-RAY DIFFRACTIONr_bond_other_d0.0020.0164412
X-RAY DIFFRACTIONr_angle_refined_deg1.6471.6576138
X-RAY DIFFRACTIONr_angle_other_deg1.2531.59410170
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5075548
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.85422.381210
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.08715810
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.3611524
X-RAY DIFFRACTIONr_chiral_restr0.070.2568
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024990
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021000
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_it1.8243.2872204
X-RAY DIFFRACTIONr_mcbond_other1.8223.2852203
X-RAY DIFFRACTIONr_mcangle_it3.1264.9152748
X-RAY DIFFRACTIONr_mcangle_other3.1264.9182749
X-RAY DIFFRACTIONr_scbond_it1.8193.4722328
X-RAY DIFFRACTIONr_scbond_other1.8183.4742329
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.085.1543391
X-RAY DIFFRACTIONr_long_range_B_refined5.84637.9964958
X-RAY DIFFRACTIONr_long_range_B_other5.84838.0154959
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 8576 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.03 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.369 38 -
Rwork0.323 1258 -
obs--99.16 %
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)
11.4108-1.2995-0.03918.88953.4363.41460.2522-0.13250.6577-0.1896-0.06140.6161-0.9332-0.0036-0.19090.98080.00080.07860.51440.01451.1766-34.55024.9983-27.1932
21.26462.11941.38626.48072.92211.65540.06430.14990.04610.534-0.1160.14760.18140.01360.05170.4735-0.0492-0.01110.5538-0.02020.4473-10.646813.0236-18.3726
33.50760.29140.99693.77280.24133.43190.0060.0449-0.0319-0.03930.0586-0.2588-0.10070.1166-0.06450.3805-0.0097-0.23310.0081-0.01860.2505-15.2158-14.1482-27.011
42.93993.2494-0.06967.6919-1.05641.3781-0.1166-0.0973-0.99270.5985-0.0633-0.06420.6789-0.13440.181.26050.03910.09730.55310.04311.1462-4.78157.72819.5772
53.4055.76693.534511.17025.94113.6822-0.0325-0.13940.2489-0.1068-0.23850.8366-0.0642-0.06470.27090.5485-0.0476-0.11780.5766-0.06960.5427-8.4656-0.2926-15.6339
62.88110.19391.06353.73960.41894.2625-0.01660.0775-0.1142-0.2470.0439-0.1029-0.00610.019-0.02730.299-0.0152-0.27250.0112-0.01730.3614-0.962326.8783-9.351
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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