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- PDB-9czu: HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex w... -

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Basic information

Entry
Database: PDB / ID: 9czu
TitleHPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with compound 9
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / Kinase / 3D domain swap / inactive state
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: 1.85 Å
AuthorsJohnson, E. / Mc Tigue, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.
Authors: Gallego, R.A. / Cho-Schultz, S. / Del Bel, M. / Dechert-Schmitt, A.M. / Donaldson, J.S. / He, M. / Jalaie, M. / Kania, R. / Matthews, J. / McTigue, M. / Tuttle, J.B. / Risley, H. / Zhou, D. ...Authors: Gallego, R.A. / Cho-Schultz, S. / Del Bel, M. / Dechert-Schmitt, A.M. / Donaldson, J.S. / He, M. / Jalaie, M. / Kania, R. / Matthews, J. / McTigue, M. / Tuttle, J.B. / Risley, H. / Zhou, D. / Zhou, R. / Ahmad, O.K. / Bernier, L. / Berritt, S. / Braganza, J. / Chen, Z. / Cianfrogna, J.A. / Collins, M. / Costa Jones, C. / Cronin, C.N. / Davis, C. / Dress, K. / Edwards, M. / Farrell, W. / France, S.P. / Grable, N. / Johnson, E. / Johnson, T.W. / Jones, R. / Knauber, T. / Lafontaine, J. / Loach, R.P. / Maestre, M. / Miller, N. / Moen, M. / Monfette, S. / Morse, P. / Nager, A.R. / Niosi, M. / Richardson, P. / Rohner, A.K. / Sach, N.W. / Timofeevski, S. / Tucker, J.W. / Vetelino, B. / Zhang, L. / Nair, S.K.
History
DepositionAug 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 8, 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
B: Mitogen-activated protein kinase kinase kinase kinase 1
C: Mitogen-activated protein kinase kinase kinase kinase 1
D: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,9579
Polymers138,0204
Non-polymers1,9385
Water12,088671
1
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)70,0275
Polymers69,0102
Non-polymers1,0173
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4260 Å2
ΔGint-34 kcal/mol
Surface area26000 Å2
MethodPISA
2
C: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules

D: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,9314
Polymers69,0102
Non-polymers9212
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_554x,y,z-11
Buried area4180 Å2
ΔGint-42 kcal/mol
Surface area26470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.190, 84.260, 87.320
Angle α, β, γ (deg.)67.33, 73.51, 76.15
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Mitogen-activated protein kinase kinase kinase kinase 1 / Hematopoietic progenitor kinase / MAPK/ERK kinase kinase kinase 1 / MEKKK 1


Mass: 34504.887 Da / Num. of mol.: 4 / Mutation: T165E, S171E
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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-A1A1D / 6-methoxy-4-[(methylamino)methyl]-2-(6-{4-[(2S)-4,4,4-trifluorobutan-2-yl]-4H-1,2,4-triazol-3-yl}pyridin-2-yl)-2,3-dihydro-1H-isoindol-1-one


Mass: 460.452 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H23F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 671 / 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: 2.71 Å3/Da / Density % sol: 54.69 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion, sitting drop
Details: Well volume: 30.0 uL Well Ingredients: Buffer: 0.1 M (3.0 uL of stock 1.0 M) Tris (pH 8.00) Salt: 0.01 M (0.6 uL of stock 0.5 M) Magnesium sulfate hydrate Precipitant: 17.0 %w/v (7. ...Details: Well volume: 30.0 uL Well Ingredients: Buffer: 0.1 M (3.0 uL of stock 1.0 M) Tris (pH 8.00) Salt: 0.01 M (0.6 uL of stock 0.5 M) Magnesium sulfate hydrate Precipitant: 17.0 %w/v (7.1830985915 uL of stock 71.0 %w/v) 1,6 hexanediol Additive: 0.02 M (6.0 uL of stock 0.1 M) Barium Acetate Plate setup temperature: 13 C Plate incubation temperature: 13 C Drop volume from well: 0.3 uL Drop protein volume: 0.2 uL 15mg/ml

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→78.71 Å / Num. obs: 67438 / % possible obs: 88.1 % / Redundancy: 3.5 % / CC1/2: 0.995 / Net I/σ(I): 9.9
Reflection shellResolution: 1.85→2.13 Å / Num. unique obs: 3372 / CC1/2: 0.54

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
STARANISOdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→78.71 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.263 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.262 / SU Rfree Blow DPI: 0.212 / SU Rfree Cruickshank DPI: 0.214
RfactorNum. reflection% reflectionSelection details
Rfree0.248 3427 5.08 %RANDOM
Rwork0.195 ---
obs0.198 67437 54.1 %-
Displacement parametersBiso mean: 45.35 Å2
Baniso -1Baniso -2Baniso -3
1--1.1051 Å20.5332 Å20.06 Å2
2--1.4811 Å2-0.3408 Å2
3----0.3761 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 1.85→78.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8995 0 137 671 9803
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019453HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0812870HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3322SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1547HARMONIC5
X-RAY DIFFRACTIONt_it9453HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.95
X-RAY DIFFRACTIONt_other_torsion19.94
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1177SEMIHARMONIC5
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_contact11186SEMIHARMONIC4
LS refinement shellResolution: 1.85→1.9 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2829 -4.2 %
Rwork0.2299 114 -
all0.2331 119 -
obs--1.28 %

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