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- PDB-9qt6: Crystal structure of HPK1 T165E/S171E in complex with pyrazine ca... -

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Basic information

Entry
Database: PDB / ID: 9qt6
TitleCrystal structure of HPK1 T165E/S171E in complex with pyrazine carboxamide inhibitor
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE
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: 1.76 Å
AuthorsSchimpl, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To be published
Title: Synthetic Chemistry Driving the Discovery and Development of a Series of Pyrazoles as HPK1 Inhibitors
Authors: Metrano, A.J.
History
DepositionApr 8, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 28, 2025Provider: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4033
Polymers32,9481
Non-polymers4542
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.190, 68.100, 58.430
Angle α, β, γ (deg.)90.00, 96.33, 90.00
Int Tables number5
Space group name H-MC121

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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: 32948.223 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: activating mutations S171E, T165E / 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-A1JAF / 3-[(1,3-dimethylpyrazol-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide


Mass: 392.418 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20N10O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 2.29 Å3/Da / Density % sol: 46.2 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 30 % PEG400, 0.2 M tri-sodium citrate, 0.01 M propionate-cacodylate-bis-tris (PCTP) buffer pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.98011 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Dec 6, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98011 Å / Relative weight: 1
ReflectionResolution: 1.76→58.074 Å / Num. obs: 21534 / % possible obs: 73.2 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.041 / Rrim(I) all: 0.077 / Net I/σ(I): 10.1
Reflection shellResolution: 1.762→1.938 Å / % possible obs: 14.8 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.932 / Num. measured all: 3645 / Num. unique obs: 1077 / Rpim(I) all: 0.587 / Rrim(I) all: 1.105 / Net I/σ(I) obs: 1.3

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
Aimlessdata scaling
STARANISOdata scaling
BUSTER2.11.7refinement
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.76→50.64 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.941 / SU R Cruickshank DPI: 0.172 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.169 / SU Rfree Blow DPI: 0.145 / SU Rfree Cruickshank DPI: 0.147
RfactorNum. reflection% reflectionSelection details
Rfree0.226 1079 5.01 %RANDOM
Rwork0.196 ---
obs0.198 21533 73.3 %-
Displacement parametersBiso mean: 38.06 Å2
Baniso -1Baniso -2Baniso -3
1--1.6454 Å20 Å2-1.164 Å2
2--0.4915 Å20 Å2
3---1.1539 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.76→50.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2241 0 33 121 2395
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012337HARMONIC2
X-RAY DIFFRACTIONt_angle_deg13163HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d812SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes386HARMONIC5
X-RAY DIFFRACTIONt_it2337HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion17.64
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion293SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2752SEMIHARMONIC4
LS refinement shellResolution: 1.76→1.89 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.203 -6.96 %
Rwork0.2078 401 -
all0.2074 431 -
obs--8.14 %
Refinement TLS params.Method: refined / Origin x: 16.284 Å / Origin y: 0.005 Å / Origin z: 10.9611 Å
111213212223313233
T-0.0968 Å2-0.0098 Å2-0.0165 Å2--0.0654 Å20.0144 Å2---0.043 Å2
L1.2429 °2-0.0783 °2-0.3284 °2-0.8737 °20.0716 °2--1.2446 °2
S0.042 Å °-0.1159 Å °-0.0472 Å °0.1076 Å °-0.0028 Å °-0.0375 Å °0.0187 Å °-0.0206 Å °-0.0392 Å °
Refinement TLS groupSelection details: { A|* }

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