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- PDB-9bik: Crystal structure of inhibitor 1 bound to HPK1 -

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Basic information

Entry
Database: PDB / ID: 9bik
TitleCrystal structure of inhibitor 1 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
: / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsKiefer, J.T. / Tellis, J.C. / Chan, B.K. / Wang, W. / Wu, P. / Siu, M. / Heffron, T.P. / Choo, E.F.
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 23, 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)71,28213
Polymers70,0372
Non-polymers1,24511
Water5,495305
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5970 Å2
ΔGint-13 kcal/mol
Surface area28160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.657, 56.589, 84.979
Angle α, β, γ (deg.)90.000, 98.610, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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: 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
#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-A1APO / (1S,2S)-N-[(6P)-8-amino-6-(4-methylpyridin-3-yl)isoquinolin-3-yl]-2-cyanocyclopropane-1-carboxamide


Mass: 343.382 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H17N5O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 305 / Source method: isolated from a natural source / Formula: H2O
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: 2.33 Å3/Da / Density % sol: 47.22 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop / pH: 8.5
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: Sep 17, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. obs: 204275 / % possible obs: 99 % / Redundancy: 6.7 % / Biso Wilson estimate: 30.99 Å2 / CC1/2: 0.79 / Rmerge(I) obs: 0.106 / Net I/σ(I): 17.2
Reflection shellResolution: 2.25→2.33 Å / Rmerge(I) obs: 0.746 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2939 / CC1/2: 0.79

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.25→33.94 Å / SU ML: 0.2581 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.6143
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2444 1488 5.2 %
Rwork0.1959 27116 -
obs0.1985 28604 92.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.39 Å2
Refinement stepCycle: LAST / Resolution: 2.25→33.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4489 0 88 305 4882
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00434676
X-RAY DIFFRACTIONf_angle_d0.6546306
X-RAY DIFFRACTIONf_chiral_restr0.0407700
X-RAY DIFFRACTIONf_plane_restr0.004789
X-RAY DIFFRACTIONf_dihedral_angle_d10.5259629
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.320.3422990.26261729X-RAY DIFFRACTION65.31
2.32-2.410.2869990.24362001X-RAY DIFFRACTION75.54
2.41-2.50.26341390.23962241X-RAY DIFFRACTION85.98
2.5-2.620.35281350.22622546X-RAY DIFFRACTION96.27
2.62-2.750.2931260.22822649X-RAY DIFFRACTION99
2.75-2.930.27691500.22842593X-RAY DIFFRACTION99.31
2.93-3.150.27161400.21912666X-RAY DIFFRACTION99.26
3.15-3.470.24931330.19512635X-RAY DIFFRACTION99.53
3.47-3.970.22861460.16952655X-RAY DIFFRACTION99.57
3.97-50.18991550.15112677X-RAY DIFFRACTION99.61
5-33.940.21771660.19232724X-RAY DIFFRACTION99.69
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)
10.918548319971-0.3510915172130.6526151788932.47268380308-0.4685367365121.824207834970.09120247564190.0477961295013-0.20776415693-0.0657167665080.00278045574964-0.2580579631340.266392176428-0.3972055005760.004780633129210.1816292014450.0307497955086-0.03399804936490.337163655836-0.004767438866190.27801708086814.922289394113.48844238646.3358552838
20.02778028265990.0130660336454-0.0683275020276-0.0111776925956-0.02430529331290.359074593224-0.2333592938940.0465177212736-0.344277709586-0.1503609464480.111241449340.11812752804-0.0195349186157-0.5042996454060.02436316202510.3321243311420.0255552795520.02266960917010.421443399097-0.01389882053170.29703506069714.044223852923.763305422128.9478630016
30.5118616723020.02055191699331.022621056990.3080096801390.2351896485832.282150263470.03130222966050.1584040264690.273699199704-0.0873744907754-0.2143004830060.310690950613-0.466719870717-1.32188663299-0.7373368606830.3973578070850.518824390879-0.03854026233840.8945258209890.03489477386710.3118544932320.72885658675231.862570724143.0412280418
40.3743058184630.00943067394026-0.1810272814740.6022601927540.1041249136110.312324529832-0.0840123936193-0.238168760023-0.5019518234590.5498646838540.06023340030080.09840959348990.637350659659-0.6009669541940.001512346242070.647943682927-0.2134804176140.03504091986820.5101700570540.01673088177130.6512171341079.428830801992.37074892393-0.2976347496
50.735789257086-0.7915400527320.2748131679280.89744093462-0.2686676333533.258864502120.08432842045180.0490427330136-0.285349563964-0.0095636846607-0.02535642670940.09844704712510.0494359591588-0.7504662001220.2760520578740.158835859360.01637843274880.01002041898350.120418224954-0.03608553208260.21672599905218.900394253818.1142847414-2.83670290785
62.323647936021.88687274839-2.383716085231.60958833749-1.794819356612.67476424231-0.543893542529-0.161308538354-0.582304188656-0.4164187739650.351557787142-0.2432343246960.6076873347-0.764283808047-0.1369185545250.4501332006860.0863557236552-0.004088058981540.5374597175490.0539440308530.3560979873425.6609039742520.023640656522.811268706
71.883861819050.397994126439-0.2377759607081.943307206210.02565406321541.129310623110.205722736315-0.2132868533750.1920577242210.179879561186-0.149956505384-0.158850831233-0.7318296690150.0736700625940.01114266869710.3132564686860.06717713316630.04166437159660.0380674090223-0.0008646125122670.20103116975326.224642033229.04708294753.12855301105
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 6 through 153 )AA6 - 1531 - 146
22chain 'A' and (resid 154 through 210 )AA154 - 210147 - 194
33chain 'A' and (resid 211 through 296 )AA211 - 296195 - 280
44chain 'B' and (resid 4 through 85 )BB4 - 851 - 80
55chain 'B' and (resid 86 through 156 )BB86 - 15681 - 151
66chain 'B' and (resid 157 through 193 )BB157 - 193152 - 188
77chain 'B' and (resid 194 through 294 )BB194 - 294189 - 289

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