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

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Basic information

Entry
Database: PDB / ID: 9czx
TitleHPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with compound 21
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 / cell population proliferation / protein phosphorylation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / cell population proliferation / protein phosphorylation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction / 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: 1.464 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

Downloads & links

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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)70,4636
Polymers69,0102
Non-polymers1,4534
Water7,530418
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4750 Å2
ΔGint-43 kcal/mol
Surface area26450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.73, 68.28, 72.15
Angle α, β, γ (deg.)90, 104.56, 90
Int Tables number4
Space group name H-MP1211

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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.: 2 / Mutation: T165E, S171E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP4K1, HPK1 / Production host: Spodoptera frugiperda ascovirus 1a
References: UniProt: Q92918, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A1A1B / 4-[(1R)-1-aminopropyl]-2-{6-[(4S,5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one


Mass: 472.585 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H32N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 418 / 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: 2.34 Å3/Da / Density % sol: 47.43 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion, sitting drop
Details: Well Ingredients: Precipitant: 20.0 %v/v (5.0 uL of stock 100.0 %v/v) Ethylene glycol Precipitant: 10.0 %w/v (5.0 uL of stock 50.0 %w/v) PEG 4000 Salt: 0.1 M (0.5 uL of stock 5.0 M) Sodium ...Details: Well Ingredients: Precipitant: 20.0 %v/v (5.0 uL of stock 100.0 %v/v) Ethylene glycol Precipitant: 10.0 %w/v (5.0 uL of stock 50.0 %w/v) PEG 4000 Salt: 0.1 M (0.5 uL of stock 5.0 M) Sodium chloride Buffer: 0.1 M (2.5 uL of stock 1.0 M) MES (pH 6.00) Plate setup temperature: 13 C Plate incubation temperature: 13 C Drop volume from well: 0.13 uL Drop protein volume: 0.21045454545454545 uL Protein concentration 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 EIGER2 S 9M / Detector: PIXEL / Date: Sep 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.46→69.83 Å / Num. obs: 67520 / % possible obs: 89.7 % / Redundancy: 6.9 % / CC1/2: 0.998 / Net I/σ(I): 14.8
Reflection shellResolution: 1.46→1.64 Å / Num. unique obs: 3377 / CC1/2: 0.506

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
STARANISOdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.464→69.83 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.941 / SU R Cruickshank DPI: 0.121 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.123 / SU Rfree Blow DPI: 0.114 / SU Rfree Cruickshank DPI: 0.114
RfactorNum. reflection% reflectionSelection details
Rfree0.2422 3434 -RANDOM
Rwork0.215 ---
obs0.2164 67520 61.6 %-
Displacement parametersBiso mean: 33.82 Å2
Baniso -1Baniso -2Baniso -3
1-0.4628 Å20 Å20.1499 Å2
2--0.3373 Å20 Å2
3----0.8001 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.464→69.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4534 0 106 418 5058
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0094849HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.986663HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1655SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes811HARMONIC5
X-RAY DIFFRACTIONt_it4750HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion597SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4404SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.25
X-RAY DIFFRACTIONt_other_torsion17.34
LS refinement shellResolution: 1.464→1.58 Å
RfactorNum. reflection% reflection
Rfree0.2612 68 -
Rwork0.2088 --
obs--6.25 %

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