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- PDB-7r9l: Crystal structure of HPK1 in complex with compound 2 -

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Basic information

Entry
Database: PDB / ID: 7r9l
TitleCrystal structure of HPK1 in complex with compound 2
ComponentsHematopoietic progenitor kinase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / inhibitor / MAP4K1 / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / positive regulation of MAPK cascade / non-specific serine/threonine protein kinase / intracellular signal transduction / protein phosphorylation ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / cell population proliferation / positive regulation of MAPK cascade / 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
Chem-2YE / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.332 Å
AuthorsWu, P. / Lehoux, I. / Wang, W.
CitationJournal: Acs Med.Chem.Lett. / Year: 2022
Title: Discovery of Spiro-azaindoline Inhibitors of Hematopoietic Progenitor Kinase 1 (HPK1).
Authors: Chan, B.K. / Seward, E. / Lainchbury, M. / Brewer, T.F. / An, L. / Blench, T. / Cartwright, M.W. / Chan, G.K.Y. / Choo, E.F. / Drummond, J. / Elliott, R.L. / Gancia, E. / Gazzard, L. / Hu, B. ...Authors: Chan, B.K. / Seward, E. / Lainchbury, M. / Brewer, T.F. / An, L. / Blench, T. / Cartwright, M.W. / Chan, G.K.Y. / Choo, E.F. / Drummond, J. / Elliott, R.L. / Gancia, E. / Gazzard, L. / Hu, B. / Jones, G.E. / Luo, X. / Madin, A. / Malhotra, S. / Moffat, J.G. / Pang, J. / Salphati, L. / Sneeringer, C.J. / Stivala, C.E. / Wei, B. / Wang, W. / Wu, P. / Heffron, T.P.
History
DepositionJun 29, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 5, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 9, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hematopoietic progenitor kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4012
Polymers33,1201
Non-polymers2801
Water1086
1
A: Hematopoietic progenitor kinase
hetero molecules

A: Hematopoietic progenitor kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,8014
Polymers66,2412
Non-polymers5612
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4900 Å2
ΔGint-32 kcal/mol
Surface area24890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.890, 96.790, 76.330
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Hematopoietic progenitor kinase / HKP1 / Hematopoietic progenitor kinase / MAPK/ERK kinase kinase kinase 1 / MEKKK 1


Mass: 33120.410 Da / Num. of mol.: 1
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-2YE / 2-amino-N,N-dimethyl-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide


Mass: 280.324 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.53 Å3/Da / Density % sol: 51.47 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop
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: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 11, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.33→66.257 Å / Num. obs: 8574 / % possible obs: 92 % / Redundancy: 4.2 % / Biso Wilson estimate: 44.42 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.107 / Rpim(I) all: 0.054 / Rrim(I) all: 0.12 / Net I/σ(I): 8.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.89-3.054.30.397439710270.9310.1990.4472.693
9.14-48.394.20.05910282420.9950.0290.06616.190.1

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Processing

Software
NameVersionClassification
PHENIX1.12-2829_finalrefinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
iMOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6CQE

6cqe


Resolution: 2.332→66.257 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 31.74 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2842 456 5.32 %
Rwork0.2273 8118 -
obs0.23 8574 58.33 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 174.19 Å2 / Biso mean: 62.2799 Å2 / Biso min: 18.46 Å2
Refinement stepCycle: final / Resolution: 2.332→66.257 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2218 0 21 6 2245
Biso mean--37.45 43.88 -
Num. residues----282
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032290
X-RAY DIFFRACTIONf_angle_d0.6353095
X-RAY DIFFRACTIONf_chiral_restr0.04345
X-RAY DIFFRACTIONf_plane_restr0.003389
X-RAY DIFFRACTIONf_dihedral_angle_d10.2771370
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.3322-2.66970.36570.31991220
2.6697-3.36360.32761710.28299765
3.3636-66.2570.26282280.2054420988
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)
11.6794-0.1249-0.7210.7907-0.52370.90620.0717-0.12661.6969-0.38780.19430.2834-0.73830.05530.01280.7419-0.0247-0.0660.46830.0261.0848-32.367-1.331-22.097
20.61660.65910.2254.15381.27162.86520.0682-0.02240.02620.0720.0208-0.2168-0.16050.18680.00050.19750.05160.01440.31590.01470.2315-17.81-16.463-10.213
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 7:93 )A7 - 93
2X-RAY DIFFRACTION2( CHAIN A AND RESID 94:294 )A94 - 294

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