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- PDB-9n7r: Crystal structure of HPK1 bound to N-(3,5-difluoro-4-{[3-(trifluo... -

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Basic information

Entry
Database: PDB / ID: 9n7r
TitleCrystal structure of HPK1 bound to N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[3-(morpholin-4-yl)propyl]urea (compound C6)
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsSIGNALING PROTEIN / nucleotide binding / MAP4K1 / Mitogen-activated protein kinase kinase kinase kinase 1
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 / cell population proliferation / protein phosphorylation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / cell population proliferation / protein phosphorylation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction / 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: 2.13 Å
AuthorsWalters, B.T. / Kiefer, J.R. / Hsu, P.L. / Wang, W. / Wu, P.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Chem.Inf.Model. / Year: 2025
Title: Integrating Hydrogen Exchange with Molecular Dynamics for Improved Ligand Binding Predictions.
Authors: Walters, B.T. / Patapoff, A.W. / Kiefer, J.R. / Wu, P. / Wang, W.
History
DepositionFeb 6, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 2, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)73,34119
Polymers70,0372
Non-polymers3,30417
Water4,179232
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8230 Å2
ΔGint-3 kcal/mol
Surface area26190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.190, 76.690, 85.870
Angle α, β, γ (deg.)90.00, 95.82, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#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: 35018.434 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

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Non-polymers , 5 types, 249 molecules

#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-A1BWC / N-(3,5-difluoro-4-{[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]oxy}phenyl)-N'-[3-(morpholin-4-yl)propyl]urea


Mass: 499.434 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C22H22F5N5O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.25 Å3/Da / Density % sol: 45.43 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 12% PEG8000

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11583 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 16, 2019
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11583 Å / Relative weight: 1
ReflectionResolution: 2.13→47.94 Å / Num. obs: 34882 / % possible obs: 99.9 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.037 / Rrim(I) all: 0.095 / Χ2: 1.05 / Net I/σ(I): 14.1 / Num. measured all: 233514
Reflection shellResolution: 2.13→2.19 Å / % possible obs: 99.8 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.811 / Num. measured all: 19926 / Num. unique obs: 2879 / CC1/2: 0.817 / Rpim(I) all: 0.332 / Rrim(I) all: 0.878 / Χ2: 1.01 / Net I/σ(I) obs: 2.7

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimless0.7.4 (CCP4 7.0.71)data scaling
XDSdata reduction
PHENIX1.20.1_4487phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.13→47.94 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.78 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2268 1699 4.9 %4.90%
Rwork0.1783 ---
obs0.1807 34675 99.29 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.13→47.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4555 0 212 232 4999
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0054873
X-RAY DIFFRACTIONf_angle_d0.7746579
X-RAY DIFFRACTIONf_dihedral_angle_d18.681800
X-RAY DIFFRACTIONf_chiral_restr0.042703
X-RAY DIFFRACTIONf_plane_restr0.005812
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.13-2.190.31671560.25092757X-RAY DIFFRACTION100
2.19-2.260.29581370.23742717X-RAY DIFFRACTION100
2.26-2.340.28761180.2212743X-RAY DIFFRACTION99
2.34-2.440.26381350.21942756X-RAY DIFFRACTION99
2.44-2.550.27011500.20162752X-RAY DIFFRACTION99
2.55-2.680.271310.19122761X-RAY DIFFRACTION100
2.68-2.850.24431510.18992731X-RAY DIFFRACTION100
2.85-3.070.27261500.20562713X-RAY DIFFRACTION99
3.07-3.380.24751450.18062748X-RAY DIFFRACTION99
3.38-3.870.19461480.16182735X-RAY DIFFRACTION99
3.87-4.870.18771280.13452768X-RAY DIFFRACTION98
4.88-47.940.18931500.17112795X-RAY DIFFRACTION99
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)
12.2062-0.5436-0.86951.8211-1.11741.66380.1522-0.00430.37550.15240.05320.1397-0.2446-0.206900.31840.0104-0.00590.388-0.01860.3911.501822.271510.8102
20.57990.3160.58230.7513-0.32690.8860.0108-0.4749-0.00440.37650.0039-0.0725-0.1277-0.1333-00.3419-0.0014-0.00750.411-0.04120.33777.549717.981221.9746
31.7958-0.4598-0.06131.1298-0.28390.69320.0411-0.09360.1394-0.0095-0.065-0.0149-0.0349-0.04400.2118-0.0123-0.02120.2275-0.00760.251218.709413.41228.1306
40.89060.6144-1.9525-0.1331-0.65710.5155-0.0272-0.111-0.03730.2278-0.09110.09480.03750.0514-0.00020.3827-0.00720.02160.39920.01740.368813.97242.336919.7189
51.4803-0.2529-0.56342.33221.01591.9226-0.1165-0.1119-0.18880.0765-0.0293-0.14010.35490.1351-0.00010.23120.0412-0.00730.27680.02420.302330.8687-0.71817.8207
60.7593-0.0372-0.08720.4864-0.02510.0755-0.15140.6518-0.2789-0.8684-0.09990.1454-0.0909-0.19420.00830.450.02150.02430.36160.01140.443220.803116.6494-8.6898
70.60580.21830.10391.4189-0.60443.1941-0.03220.55090.0181-0.50070.3061-0.26390.7139-0.0023-00.7014-0.0434-0.06660.6821-0.05350.5885-0.7702-26.896117.2662
81.86830.72330.60252.5929-0.51382.31930.08270.2872-0.0847-0.0420.06240.09440.2493-0.0054-0.00250.44140.02450.00120.33230.0060.2624-0.4912-20.908534.037
90.13540.8227-1.210.1794-1.07040.3942-0.0681-0.083-0.34930.18-0.0878-0.07890.0991-0.21780.00030.4987-0.04750.0390.44440.02080.45712.1229-10.550419.6633
100.90480.47130.08443.5502-0.30281.97850.1846-0.09250.07330.4611-0.1266-0.1179-0.08860.1449-00.43510.01160.02240.3405-0.00280.26493.4915-10.575944.1582
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 6 through 49 )
2X-RAY DIFFRACTION2chain 'A' and (resid 50 through 83 )
3X-RAY DIFFRACTION3chain 'A' and (resid 84 through 150 )
4X-RAY DIFFRACTION4chain 'A' and (resid 151 through 210 )
5X-RAY DIFFRACTION5chain 'A' and (resid 211 through 280 )
6X-RAY DIFFRACTION6chain 'A' and (resid 281 through 296 )
7X-RAY DIFFRACTION7chain 'B' and (resid 8 through 83 )
8X-RAY DIFFRACTION8chain 'B' and (resid 84 through 150 )
9X-RAY DIFFRACTION9chain 'B' and (resid 151 through 193 )
10X-RAY DIFFRACTION10chain 'B' and (resid 194 through 294 )

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