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- PDB-9h8f: Crystal structure of HPK1 T165E/S171E in complex with pyrazine ca... -

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Basic information

Entry
Database: PDB / ID: 9h8f
TitleCrystal structure of HPK1 T165E/S171E in complex with pyrazine carboxamide inhibitor AZ3246 (compound 24)
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / Kinase / type 1 inhibitor / structure-based drug design
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 / positive regulation of MAPK cascade / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 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 / positive regulation of MAPK cascade / 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 / 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: 1.393 Å
AuthorsSchimpl, M. / Pflug, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor.
Authors: Shields, J.D. / Baker, D. / Balazs, A.Y.S. / Bommakanti, G. / Casella, R. / Cao, S. / Cook, S. / Escobar, R.A. / Fawell, S. / Gibbons, F.D. / Giblin, K.A. / Goldberg, F.W. / Gosselin, E. / ...Authors: Shields, J.D. / Baker, D. / Balazs, A.Y.S. / Bommakanti, G. / Casella, R. / Cao, S. / Cook, S. / Escobar, R.A. / Fawell, S. / Gibbons, F.D. / Giblin, K.A. / Goldberg, F.W. / Gosselin, E. / Grebe, T. / Hariparsad, N. / Hatoum-Mokdad, H. / Howells, R. / Hughes, S.J. / Jackson, A. / Karapa Reddy, I. / Kettle, J.G. / Lamont, G.M. / Lamont, S. / Li, M. / Lill, S.O.N. / Mele, D.A. / Metrano, A.J. / Mfuh, A.M. / Morrill, L.A. / Peng, B. / Pflug, A. / Proia, T.A. / Rezaei, H. / Richards, R. / Richter, M. / Robbins, K.J. / San Martin, M. / Schimpl, M. / Schuller, A.G. / Sha, L. / Shen, M. / Sheppeck 2nd, J.E. / Singh, M. / Stokes, S. / Song, K. / Sun, Y. / Tang, H. / Wagner, D.J. / Wang, J. / Wang, Y. / Wilson, D.M. / Wu, A. / Wu, C. / Wu, D. / Wu, Y. / Xu, K. / Yang, Y. / Yao, T. / Ye, M. / Zhang, A.X. / Zhang, H. / Zhai, X. / Zhou, Y. / Ziegler, R.E. / Grimster, N.P.
History
DepositionOct 29, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 19, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 5, 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

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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)33,5444
Polymers32,9481
Non-polymers5963
Water4,936274
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1240 Å2
ΔGint4 kcal/mol
Surface area13890 Å2
Unit cell
Length a, b, c (Å)78.611, 67.868, 63.669
Angle α, β, γ (deg.)90.00, 94.87, 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 / Mutation: T165E, S171E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP4K1, HPK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q92918, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1ITB / 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-[2,2,2-tris(fluoranyl)ethyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide


Mass: 471.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20F3N9O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 274 / 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: 2.57 Å3/Da / Density % sol: 52.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 6.5 % PEG8000, 0.1 M PCTP pH 8.5, co-crystallised with 1 mM inhibitor, cryoprotected with 20 % ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Oct 5, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.393→63.44 Å / Num. obs: 39592 / % possible obs: 59.4 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.038 / Rpim(I) all: 0.024 / Rrim(I) all: 0.045 / Net I/σ(I): 9.9
Reflection shellResolution: 1.393→1.542 Å / % possible obs: 11.4 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.56 / Num. measured all: 6834 / Num. unique obs: 1980 / Rpim(I) all: 0.349 / Rrim(I) all: 0.661 / Net I/σ(I) obs: 1.7

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (24-FEB-2021)refinement
STARANISOdata scaling
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.393→63.44 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.695 / SU R Cruickshank DPI: 0.099 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.102 / SU Rfree Blow DPI: 0.106 / SU Rfree Cruickshank DPI: 0.104
RfactorNum. reflection% reflectionSelection details
Rfree0.2463 1953 4.93 %RANDOM
Rwork0.2011 ---
obs0.2033 39578 59.5 %-
Displacement parametersBiso mean: 27.05 Å2
Baniso -1Baniso -2Baniso -3
1--0.7971 Å20 Å2-1.2254 Å2
2---0.2981 Å20 Å2
3---1.0952 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: 1 / Resolution: 1.393→63.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2269 0 42 274 2585
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082361HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.93193HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d831SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes388HARMONIC5
X-RAY DIFFRACTIONt_it2361HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.43
X-RAY DIFFRACTIONt_other_torsion15.98
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion294SEMIHARMONIC5
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_contact2354SEMIHARMONIC4
LS refinement shellResolution: 1.393→1.49 Å
RfactorNum. reflection% reflection
Rfree0.2412 -6.31 %
Rwork0.2544 742 -
obs--6.61 %
Refinement TLS params.Method: refined / Origin x: 16.7982 Å / Origin y: -0.0579 Å / Origin z: 11.4767 Å
111213212223313233
T-0.0257 Å20.0244 Å2-0.0071 Å2--0.0297 Å20.0076 Å2--0.0054 Å2
L0.9605 °2-0.0348 °20.278 °2-1.218 °2-0.023 °2--0.8502 °2
S-0.063 Å °-0.1246 Å °-0.0093 Å °0.1723 Å °0.054 Å °0.0366 Å °-0.0748 Å °-0.0663 Å °0.0089 Å °
Refinement TLS groupSelection details: { A|* }

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