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- PDB-7m0m: HPK1 IN COMPLEX WITH COMPOUND 1 -

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Basic information

Entry
Database: PDB / ID: 7m0m
TitleHPK1 IN COMPLEX WITH COMPOUND 1
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE inhibitor / HPK1 HEMATOPOIETIC PROGENITOR KINASE / TRANSFERASE / 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 / cell population proliferation / positive regulation of MAPK cascade / protein autophosphorylation / 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 / cell population proliferation / positive regulation of MAPK cascade / protein autophosphorylation / 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. / Protein kinase domain profile. ...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-YK1 / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsLesburg, C.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Discovery of Diaminopyrimidine Carboxamide HPK1 Inhibitors as Preclinical Immunotherapy Tool Compounds.
Authors: Vara, B.A. / Levi, S.M. / Achab, A. / Candito, D.A. / Fradera, X. / Lesburg, C.A. / Kawamura, S. / Lacey, B.M. / Lim, J. / Methot, J.L. / Xu, Z. / Xu, H. / Smith, D.M. / Piesvaux, J.A. / ...Authors: Vara, B.A. / Levi, S.M. / Achab, A. / Candito, D.A. / Fradera, X. / Lesburg, C.A. / Kawamura, S. / Lacey, B.M. / Lim, J. / Methot, J.L. / Xu, Z. / Xu, H. / Smith, D.M. / Piesvaux, J.A. / Miller, J.R. / Bittinger, M. / Ranganath, S.H. / Bennett, D.J. / DiMauro, E.F. / Pasternak, A.
History
DepositionMar 11, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 7, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 6, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,7834
Polymers65,8022
Non-polymers9812
Water6,305350
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3780 Å2
ΔGint-32 kcal/mol
Surface area27670 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.168, 56.994, 63.459
Angle α, β, γ (deg.)86.730, 86.630, 67.060
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: VAL / Beg label comp-ID: VAL / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: _ / Auth seq-ID: 3 - 292 / Label seq-ID: 2 - 291

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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


Mass: 32901.207 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN
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-YK1 / 4-[2-fluoro-6-(trifluoromethyl)anilino]-2-[(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidine-5-carboxamide


Mass: 490.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H22F4N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 350 / 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: 2.58 Å3/Da / Density % sol: 52.33 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 20 mM Tris pH 8.0 , 150 mM NaCl , 5% Glycerol , 2 mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.93→63.31 Å / Num. obs: 48216 / % possible obs: 97.3 % / Redundancy: 2.2 % / Biso Wilson estimate: 41.083 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.051 / Rsym value: 0.039 / Χ2: 0.999 / Net I/σ(I): 13.66
Reflection shellResolution: 1.93→2.18 Å / Redundancy: 2.3 % / Mean I/σ(I) obs: 2.52 / Num. unique obs: 157 / CC1/2: 1 / Rrim(I) all: 0.576 / Rsym value: 0.442 / % possible all: 96.1

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PREVIOUSLY SOLVED STRUCTURE

Resolution: 1.93→63.31 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.957 / SU B: 10.178 / SU ML: 0.144 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.161 / ESU R Free: 0.143 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2198 2211 4.6 %RANDOM
Rwork0.1861 ---
obs0.1877 46005 97.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 120 Å2 / Biso mean: 46.723 Å2 / Biso min: 22.44 Å2
Baniso -1Baniso -2Baniso -3
1-1.29 Å20.48 Å2-1.53 Å2
2---0.86 Å20.49 Å2
3---0.18 Å2
Refinement stepCycle: final / Resolution: 1.93→63.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4611 0 70 350 5031
Biso mean--31.43 47.68 -
Num. residues----584
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194751
X-RAY DIFFRACTIONr_bond_other_d0.0030.024573
X-RAY DIFFRACTIONr_angle_refined_deg1.5871.9896467
X-RAY DIFFRACTIONr_angle_other_deg1.266310489
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2775596
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.61523.812202
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.71415.037805
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.621523
X-RAY DIFFRACTIONr_chiral_restr0.0920.2719
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0215370
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021059
Refine LS restraints NCS

Ens-ID: 1 / Number: 6962 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.04 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.93→1.98 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.368 161 -
Rwork0.34 3322 -
all-3483 -
obs--94.42 %
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)
12.3076-0.1064-0.06684.11421.72774.78090.05260.2063-0.166-0.15580.06650.22820.2754-0.1996-0.11920.12180.0373-0.11770.1093-0.11330.237115.409-39.81624.079
20.1927-0.24290.51512.3746-4.46938.4688-0.030.14580.158-0.04070.06830.06-0.0115-0.12-0.03830.2265-0.00470.00460.26030.05060.26510.777-18.89412.715
31.20730.68141.89680.8839-1.030211.9449-0.0026-0.04-0.06-0.0371-0.1022-0.10730.19560.1720.10490.0890.0238-0.02570.17130.04510.24712.62-3.9975.75
40.0715-0.24480.57970.9662-2.1885.06530.03040.04460.00170.0276-0.04260.0274-0.02140.26440.01230.230.0227-0.03580.2880.06190.231114.971-9.40318.801
52.703-0.10290.08222.58550.27923.1165-0.0160.04420.2477-0.01640.00330.0753-0.2944-0.25840.01280.08010.0662-0.09740.0563-0.07220.20116.075-18.75641.163
63.00730.650.96794.52060.46042.53410.1174-0.1658-0.33470.05840.00750.11330.4398-0.1194-0.12480.0960.0124-0.07020.0669-0.05940.2159-12.52-12.508-2.557
71.4068-1.58613.76331.7945-4.267910.2489-0.08110.0040.00480.1104-0.0306-0.0293-0.17250.20590.11160.26430.0132-0.01310.27050.02530.1906-0.515-14.91318.868
82.214.5395-3.21499.4413-7.139912.2846-0.21010.29620.1555-0.37850.59230.2571-0.1727-1.0564-0.38220.16610.131-0.11370.28830.00520.25786.77-14.50934.08
90.1232-0.45570.9521.7292-3.57467.4588-0.0015-0.1007-0.03-0.03010.26260.13090.1335-0.6676-0.26110.30440.0238-0.03830.37840.01920.28364.57-5.57122.268
102.17890.08060.17913.235-1.46423.592-0.09180.02120.18420.1091-0.4025-0.8323-0.01820.61980.49440.04410.016-0.12210.13280.06080.44597.5125.191-0.21
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 93
2X-RAY DIFFRACTION2A161 - 174
3X-RAY DIFFRACTION3A175 - 182
4X-RAY DIFFRACTION4A183 - 194
5X-RAY DIFFRACTION5A94 - 160
6X-RAY DIFFRACTION5A195 - 294
7X-RAY DIFFRACTION6B3 - 93
8X-RAY DIFFRACTION7B161 - 174
9X-RAY DIFFRACTION8B175 - 182
10X-RAY DIFFRACTION9B183 - 194
11X-RAY DIFFRACTION10B94 - 160
12X-RAY DIFFRACTION10B195 - 293

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