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- PDB-9bj1: Crystal structure of inhibitor GNE-6893 bound to HPK1 -

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Basic information

Entry
Database: PDB / ID: 9bj1
TitleCrystal structure of inhibitor GNE-6893 bound to HPK1
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsSIGNALING PROTEIN / HPK1 / MAP4K1 / cancer / pharmacology / kinase / inhibitor
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 / cell population proliferation / histone H3T11 kinase activity / 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
: / : / DI(HYDROXYETHYL)ETHER / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.18 Å
AuthorsKiefer, J.R. / Tellis, J.C. / Chan, B.K. / Wang, W. / Wu, P. / Choo, E.F. / Heffron, T.P. / Wei, B. / Siu, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1.
Authors: Tellis, J.C. / Wei, B. / Siu, M. / An, L. / Chan, G.K. / Chen, Y. / Du, X. / Gazzard, L. / Hu, B. / Kiefer, J. / Kakiuchi-Kiyota, S. / Lainchbury, M. / Linehan, J.L. / Luo, X. / Malhotra, S. ...Authors: Tellis, J.C. / Wei, B. / Siu, M. / An, L. / Chan, G.K. / Chen, Y. / Du, X. / Gazzard, L. / Hu, B. / Kiefer, J. / Kakiuchi-Kiyota, S. / Lainchbury, M. / Linehan, J.L. / Luo, X. / Malhotra, S. / Mendonca, R. / Pang, J. / Ran, Y. / Sethuraman, V. / Seward, E. / Sneeringer, C. / Su, D. / Wang, W. / Wu, P. / Moffat, J.G. / Heffron, T.P. / Choo, E.F. / Chan, B.K.
History
DepositionApr 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release

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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)72,17617
Polymers70,0372
Non-polymers2,14015
Water3,441191
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8350 Å2
ΔGint4 kcal/mol
Surface area26540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.483, 56.998, 61.527
Angle α, β, γ (deg.)86.670, 85.370, 66.700
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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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 , 8 types, 206 molecules

#2: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-A1APR / (9S)-2-{[(6P)-8-amino-6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl]amino}-6-methyl-5,6-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-7(8H)-one


Mass: 446.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23FN8O / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#8: Chemical ChemComp-A1APQ / (4S,5R,7R,11aP)-10-{[(3R)-3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl]ethynyl}-N~3~-methyl-6,7-dihydro-5H-5,7-methanoimidazo[2,1-a][2]benzazepine-2,3-dicarboxamide


Mass: 433.460 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23N5O4
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 191 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.36 Å3/Da / Density % sol: 47.86 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Tris-HCl, pH 8.5, 0.25 M sodium tartrate and 12% PEG 8000

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.18→50 Å / Num. obs: 31988 / % possible obs: 96.2 % / Redundancy: 2.6 % / Biso Wilson estimate: 38.75 Å2 / Rmerge(I) obs: 0.129 / Net I/σ(I): 6.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.18-2.2620.38329790.7820.9370.3140.4970.96190.1
2.26-2.352.20.34231470.8410.9560.2740.4391.0595.2
2.35-2.462.30.332680.850.9590.2320.3811.07996.5
2.46-2.582.30.2731970.8640.9630.2050.3411.09296.4
2.58-2.752.60.26332000.8950.9720.1880.3251.07696.9
2.75-2.962.80.25532060.9060.9750.1760.3111.06596.7
2.96-3.262.80.21732180.9210.9790.150.2651.07697
3.26-3.733.20.16732580.960.990.1080.1991.03597.6
3.73-4.73.10.11232520.9710.9930.0740.1351.00598.2
4.7-503.10.08132630.990.9980.0520.0971.01897.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-3000data scaling
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.18→30.65 Å / SU ML: 0.2156 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 22.9658
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2279 1568 4.9 %
Rwork0.1731 30405 -
obs0.1756 31973 95.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 47.6 Å2
Refinement stepCycle: LAST / Resolution: 2.18→30.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4537 0 141 191 4869
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00554784
X-RAY DIFFRACTIONf_angle_d0.76396477
X-RAY DIFFRACTIONf_chiral_restr0.0429712
X-RAY DIFFRACTIONf_plane_restr0.0097809
X-RAY DIFFRACTIONf_dihedral_angle_d11.782678
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.18-2.250.271260.22282431X-RAY DIFFRACTION83.89
2.25-2.330.2931850.22162714X-RAY DIFFRACTION94.74
2.33-2.420.26941670.19382725X-RAY DIFFRACTION96.37
2.42-2.530.24111540.19082780X-RAY DIFFRACTION96.17
2.53-2.670.22231270.18932807X-RAY DIFFRACTION97.02
2.67-2.830.25361500.1852806X-RAY DIFFRACTION96.57
2.83-3.050.22341450.18212773X-RAY DIFFRACTION96.91
3.05-3.360.21421450.17652817X-RAY DIFFRACTION97.05
3.36-3.850.22951020.16242867X-RAY DIFFRACTION97.6
3.85-4.840.21471480.14632827X-RAY DIFFRACTION98.35
4.84-30.650.20781190.17392858X-RAY DIFFRACTION97.86
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)
10.294851565076-0.2395516672190.1373004356810.6050513758440.6021852091160.5525204870590.03963364000630.0741416865506-0.0109643146564-0.176427778471-0.1160371430810.02553629297990.0650020559563-0.101331428691.33562296365E-50.4052483346980.0250211255062-0.009099482391450.456800339203-0.04445556686320.414539782585-2.357898713182.101261703989.67320176615
20.332767181178-0.03520361636720.2175181084830.64613571598-0.391719795460.327882790507-0.072617734351-0.03391464264220.03075691290860.0346697167005-0.00128893963461-0.0883970226738-0.0803422876554-0.0544022702973-1.18096078849E-50.3365147035470.0244523006115-0.01058893587510.332958456084-0.01102658691530.304080027932-1.2625187688424.23190015820.9812705757
30.6195118654470.1691054469190.297200508790.462764432111-0.05625250375710.2536630739630.100736145766-0.0808398071237-0.0880076799035-0.009737091637670.03979633310460.002010008075880.1687915451960.02003799123688.61079014227E-60.343154999648-0.008121808859040.003663092914950.32387855160.02518186577410.341475664567-30.295320265830.1786554944-16.4789292509
40.355131178783-0.1926226078960.272526409510.510150057981-0.3159899936120.8682424957090.006036344529360.01056754677650.110880503818-0.00620976699854-0.018635623681-0.08202609354050.03923887344290.07613530066153.17755104122E-60.289925594128-0.02321124610590.01138500211740.3045126309860.00461520639150.347312753785-10.645814853744.7044485971-11.1538583056
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11(chain 'A' and resid 3 through 95)AA3 - 951 - 93
22(chain 'A' and resid 96 through 293)AA96 - 29394 - 291
33(chain 'B' and resid 5 through 95)BB5 - 951 - 91
44(chain 'B' and resid 96 through 294)BB96 - 29492 - 290

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