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- PDB-7r9p: Crystal structure of HPK1 in complex with compound 14 -

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Basic information

Entry
Database: PDB / ID: 7r9p
TitleCrystal structure of HPK1 in complex with compound 14
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-2WI / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.27 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)67,1865
Polymers66,4132
Non-polymers7733
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4150 Å2
ΔGint-41 kcal/mol
Surface area27330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)53.258, 57.105, 61.646
Angle α, β, γ (deg.)85.770, 85.380, 67.650
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-2WI / 6-amino-2-fluoro-N,N-dimethyl-3-(4'-methylspiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridin]-5'-yl)benzamide


Mass: 338.379 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19FN4O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 2.6 Å3/Da / Density % sol: 52.69 %
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: Jun 10, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.27→45.53 Å / Num. obs: 27431 / % possible obs: 88.8 % / Redundancy: 3.9 % / Biso Wilson estimate: 40.02 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.034 / Rrim(I) all: 0.068 / Net I/σ(I): 14.3 / Num. measured all: 106277
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
2.27-2.393.90.5081529839430.8520.2960.5882.587.3
7.18-45.533.80.01933018680.9990.0120.02345.388.7

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Processing

Software
NameVersionClassification
PHENIX1.19.1-4122_finalrefinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6CQD

6cqd


Resolution: 2.27→39.12 Å / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 2 / Phase error: 25.7 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2321 1395 5.09 %
Rwork0.2096 26029 -
obs0.2108 27424 88.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 141.58 Å2 / Biso mean: 51.4334 Å2 / Biso min: 28.27 Å2
Refinement stepCycle: final / Resolution: 2.27→39.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4562 0 55 174 4791
Biso mean--50.16 49.62 -
Num. residues----578
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.27-2.350.29851500.28072511266185
2.35-2.450.32971530.2582627278091
2.45-2.560.28651450.24122649279490
2.56-2.690.29711380.25282607274589
2.69-2.860.3091290.26022418254783
2.86-3.080.25331350.24632712284792
3.08-3.390.24431400.2362646278690
3.39-3.880.22561230.19712558268187
3.88-4.890.19711400.17652704284492
4.89-39.120.18351420.17352597273989
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)
12.59991.3233-1.06621.8083-0.2131.1681-0.1617-0.3674-0.23730.25960.05010.0870.4721-0.186400.56280.0428-0.02320.4866-0.01880.5083166.43822.405-206.376
21.2773-1.23840.79780.7784-0.49843.8122-0.0242-0.11410.37490.09960.0776-0.30080.0590.40060.00010.4414-0.0098-0.01750.4598-0.04050.5551186.92835.615-201.556
32.2194-0.0928-0.7231.85471.03392.42510.10360.4549-0.4223-0.3526-0.24790.53270.578-0.2837-0.00010.71470.0219-0.03480.6439-0.13370.6018198.212-6.395-180.262
41.79970.18620.29081.2218-0.61622.7752-0.04910.15650.0942-0.1573-0.05350.1213-0.0663-0.23090.00290.38280.0133-0.00640.34990.00810.3789197.31115.686-168.445
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 5:93 )A5 - 93
2X-RAY DIFFRACTION2( CHAIN A AND RESID 94:294 )A94 - 294
3X-RAY DIFFRACTION3( CHAIN B AND RESID 3:93 )B3 - 93
4X-RAY DIFFRACTION4( CHAIN B AND RESID 94:293 )B94 - 293

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