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- PDB-7r9t: Crystal structure of HPK1 in complex with compound 17 -

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Basic information

Entry
Database: PDB / ID: 7r9t
TitleCrystal structure of HPK1 in complex with compound 17
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-2TR / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 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

Downloads & links

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Assembly

Deposited unit
A: Hematopoietic progenitor kinase
B: Hematopoietic progenitor kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,2234
Polymers66,4132
Non-polymers8102
Water11,782654
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4020 Å2
ΔGint-27 kcal/mol
Surface area27230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.257, 58.272, 61.677
Angle α, β, γ (deg.)69.910, 66.210, 68.210
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 33206.453 Da / Num. of mol.: 2
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-2TR / 6-amino-3-[(1S,3R)-4'-chloro-3-hydroxy-1',2'-dihydrospiro[cyclopentane-1,3'-pyrrolo[2,3-b]pyridin]-5'-yl]-2-fluoro-N,N-dimethylbenzamide


Mass: 404.866 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H22ClFN4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 654 / 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: 2.34 Å3/Da / Density % sol: 47.42 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / Details: 0.1 M HEPES pH 7.5 and 12% PEG 8000

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 29, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 35176 / % possible obs: 87.1 % / Redundancy: 2.2 % / Biso Wilson estimate: 20.21 Å2 / Rmerge(I) obs: 0.116 / Rpim(I) all: 0.095 / Rrim(I) all: 0.151 / Χ2: 1.177 / Net I/σ(I): 5.3 / Num. measured all: 77472
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2-2.072.10.31231310.7650.2680.4130.72177.9
2.07-2.152.20.27536270.7910.2370.3650.8189.9
2.15-2.252.20.2436320.8510.2050.3170.8590
2.25-2.372.20.20235890.8880.1720.2670.96188.6
2.37-2.522.20.16933550.9220.1440.2231.12582.9
2.52-2.712.20.14936120.9340.1250.1961.16790
2.71-2.992.20.12636440.9530.1040.1651.30290
2.99-3.422.20.10334690.9710.0830.1321.53385.6
3.42-4.312.20.08836410.9710.0710.1141.54890.6
4.31-502.20.08334760.9740.0680.1081.66885.9

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Processing

Software
NameVersionClassification
PHENIX1.19.1-4122_finalrefinement
HKL-2000data scaling
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6CQD

6cqd


Resolution: 2→46.03 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.97 / Phase error: 23.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2286 1639 4.66 %
Rwork0.1983 33527 -
obs0.1997 35166 86.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 58.33 Å2 / Biso mean: 24.468 Å2 / Biso min: 10.51 Å2
Refinement stepCycle: final / Resolution: 2→46.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4549 0 56 654 5259
Biso mean--22.99 29.5 -
Num. residues----576
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2-2.060.24491320.23652181231368
2.06-2.120.30761480.23732777292586
2.12-2.20.24071600.22652894305490
2.2-2.290.28441470.22252924307190
2.29-2.390.24961330.20752868300188
2.39-2.520.26081100.2172664277482
2.52-2.680.24051470.21112899304689
2.68-2.880.22471270.22122932305990
2.88-3.170.22131280.20332875300388
3.17-3.630.20751390.18372847298687
3.63-4.570.1931340.16212858299289
4.58-46.030.21461340.18282808294286
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)
10.8070.3582-0.07760.4003-0.38350.6615-0.02190.3097-0.0166-0.17450.0023-0.11450.07970.19910.00020.22150.0068-0.00690.27550.04240.2505-34.909-71.336254.231
20.2465-0.04030.2290.71540.55141.31070.01160.0457-0.0452-0.0293-0.00340.00440.01140.014500.13270.0007-0.01110.1176-0.00890.1427-56.947-82.02259.26
30.4737-0.00970.01310.3725-0.46740.67980.0528-0.18070.1669-0.0245-0.0754-0.34040.02380.60410.00160.29150.0282-0.00210.41210.02970.3661-34.258-118.638233.346
40.80480.0496-0.19610.66010.31891.35330.0011-0.04760.062-0.03190.0154-0.05-0.08020.08680.00030.1476-0.0012-0.00080.11230.00210.1308-56.031-106.626228.135
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 3:93 )A3 - 93
2X-RAY DIFFRACTION2( CHAIN A AND RESID 94:293 )A94 - 293
3X-RAY DIFFRACTION3( CHAIN B AND RESID 4:93 )B4 - 93
4X-RAY DIFFRACTION4( CHAIN B AND RESID 94:294 )B94 - 294

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