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- PDB-7m0l: HPK1 IN COMPLEX WITH COMPOUND 1 -

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Basic information

Entry
Database: PDB / ID: 7m0l
TitleHPK1 IN COMPLEX WITH COMPOUND 1
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE inhibiotr / HPK1 HEMATOPOIETIC PROGENITOR KINASE / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibiotr 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 / Citron homology (CNH) domain / 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 / Citron homology (CNH) domain / 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-YK4 / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.43 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
C: Mitogen-activated protein kinase kinase kinase kinase 1
D: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,2858
Polymers130,3514
Non-polymers1,9334
Water1,29772
1
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)66,1424
Polymers65,1762
Non-polymers9672
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4870 Å2
ΔGint-40 kcal/mol
Surface area27190 Å2
MethodPISA
2
C: Mitogen-activated protein kinase kinase kinase kinase 1
D: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,1424
Polymers65,1762
Non-polymers9672
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4720 Å2
ΔGint-39 kcal/mol
Surface area27320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.850, 76.723, 88.413
Angle α, β, γ (deg.)89.970, 97.840, 90.030
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASPASPLYSLYSAA7 - 2903 - 286
21ASPASPLYSLYSBB7 - 2903 - 286
12PROPROLYSLYSAA6 - 2922 - 288
22PROPROLYSLYSCC6 - 2922 - 288
13PROPROPROPROAA6 - 2942 - 290
23PROPROPROPRODD6 - 2942 - 290
14ASPASPLYSLYSBB7 - 2903 - 286
24ASPASPLYSLYSCC7 - 2903 - 286
15ASPASPLYSLYSBB7 - 2903 - 286
25ASPASPLYSLYSDD7 - 2903 - 286
16PROPROLYSLYSCC6 - 2922 - 288
26PROPROLYSLYSDD6 - 2922 - 288

NCS ensembles :
ID
1
2
3
4
5
6

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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: 32587.861 Da / Num. of mol.: 4 / 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-YK4 / 4-(2-bromoanilino)-2-[(6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino]pyrimidine-5-carboxamide


Mass: 483.361 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H23BrN6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 72 / 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: 2.32 Å3/Da / Density % sol: 46.96 %
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: SLS / Beamline: X10SA / Wavelength: 1.0001 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 28, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0001 Å / Relative weight: 1
ReflectionResolution: 2.43→87.59 Å / Num. obs: 42306 / % possible obs: 96.1 % / Redundancy: 2.2 % / Biso Wilson estimate: 61.068 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.057 / Rsym value: 0.043 / Χ2: 1.049 / Net I/σ(I): 12.89
Reflection shellResolution: 2.43→2.68 Å / Redundancy: 2.1 % / Mean I/σ(I) obs: 2.99 / Num. unique obs: 10850 / CC1/2: 0.998 / Rrim(I) all: 0.563 / Rsym value: 0.433 / % possible all: 96.2

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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: 2.43→87.59 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.903 / SU B: 38.694 / SU ML: 0.404 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.735 / ESU R Free: 0.336 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2928 980 2.3 %RANDOM
Rwork0.2459 ---
obs0.247 41326 96.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 228.98 Å2 / Biso mean: 94.047 Å2 / Biso min: 26.29 Å2
Baniso -1Baniso -2Baniso -3
1-4.31 Å20.07 Å26.36 Å2
2---3.83 Å2-0.11 Å2
3----2.15 Å2
Refinement stepCycle: final / Resolution: 2.43→87.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9102 0 124 72 9298
Biso mean--70.57 63.63 -
Num. residues----1152
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0198941
X-RAY DIFFRACTIONr_bond_other_d0.0030.028453
X-RAY DIFFRACTIONr_angle_refined_deg1.5721.98212161
X-RAY DIFFRACTIONr_angle_other_deg1.241319274
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.49451148
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.71623.819364
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.97515.0431410
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6851538
X-RAY DIFFRACTIONr_chiral_restr0.0850.21359
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02110206
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021988
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A63500.01
12B63500.01
21A64560.02
22C64560.02
31A67100.01
32D67100.01
41B65500.01
42C65500.01
51B64120.01
52D64120.01
61C64960.01
62D64960.01
LS refinement shellResolution: 2.43→2.493 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.474 60 -
Rwork0.416 3102 -
all-3162 -
obs--94.44 %
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)
19.50231.0175-4.69663.5784-2.94314.23430.30950.60340.4001-0.5402-0.2852-0.17660.05970.3121-0.02430.5398-0.14120.02690.82070.06650.832714.3918.763-5.476
27.21.5550.8330.3825-0.15352.90270.1464-0.1138-0.2871-0.0397-0.0676-0.090.22030.6344-0.07880.7240.016-0.03920.65220.00320.69276.681-13.352-16.81
37.8328-5.2581-6.52117.82060.53988.89620.4562-0.4813-0.1871-0.2416-0.29460.4082-0.49280.8452-0.16170.7062-0.07960.06430.5760.05430.510112.759-19.339-24.977
43.28680.00390.31445.97160.15753.5208-0.08330.1675-0.0817-0.2542-0.09760.04330.3168-0.02430.18090.05140.01680.05110.07360.05520.5943-6.536-6.5792.477
50.6902-0.2485-1.25552.3041-1.53129.3099-0.2443-0.6387-0.23580.78110.01550.24140.66-0.01470.22870.97080.01220.01721.0030.05061.05919.288-43.221-9.495
621.74172.177913.77940.51141.25728.7912-0.4846-0.70790.7656-0.03640.01470.184-0.32-0.42660.46990.7276-0.00710.13850.63590.10390.74746.079-19.911-10.003
71.23621.8975-2.029111.37793.14128.0069-0.2663-0.2949-0.02510.35360.12180.04651.09991.01370.14440.43560.1140.14370.6227-0.01560.5603-0.031-15.997-3.677
83.8331-0.924-0.72486.1167-0.65374.10390.15380.15870.1049-0.0663-0.07590.2221-0.3181-0.2945-0.07780.3832-0.05890.080.2071-0.00880.563716.377-28.228-33.088
90.94950.8144-0.94381.35540.11427.1298-0.12270.5658-0.2092-0.38040.1555-0.05320.4240.0508-0.03290.88940.0186-0.04240.8547-0.08010.919527.555-5.103-59.391
107.00722.09294.30921.30781.39022.6769-0.32410.1622-0.0914-0.00430.40730.0098-0.11450.1344-0.08310.71030.00920.15940.6581-0.03030.749140.1616.937-58.823
112.7851-0.9181-4.01519.2443-1.38046.6151-0.27740.1837-0.1198-0.34450.0653-0.11440.5582-0.36350.21210.453-0.090.12540.4809-0.02230.545946.50522.345-65.184
124.5491.0223-0.52526.25080.7414.48340.1441-0.08420.0759-0.0024-0.0639-0.2649-0.31150.2979-0.08030.37970.050.08860.19130.02260.549530.39410.063-36.175
138.6405-0.6195-3.85614.35073.02713.8360.2669-0.69640.29040.6449-0.30570.21090.0254-0.39830.03880.54050.14640.01860.8459-0.06630.841932.06547.138-63.409
141.3968-0.8453-2.09560.51791.29093.38450.05990.2587-0.23310.0136-0.1140.12690.2935-0.450.0540.8725-0.0333-0.13150.67710.04430.881439.49124.48-52.527
154.6063.2961-4.54639.12061.63238.03470.39210.2737-0.26310.256-0.4531-0.4184-0.4416-0.65970.06090.68920.06860.09010.5468-0.020.451233.6719.029-43.947
163.3323-0.20480.13215.84690.13243.7182-0.0903-0.13-0.08280.2508-0.0487-0.04580.32620.04260.13910.0508-0.01890.04270.0718-0.01970.59853.26131.65-71.599
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 93
2X-RAY DIFFRACTION2A161 - 173
3X-RAY DIFFRACTION2A184 - 193
4X-RAY DIFFRACTION3A174 - 183
5X-RAY DIFFRACTION4A94 - 160
6X-RAY DIFFRACTION4A195 - 294
7X-RAY DIFFRACTION5B7 - 93
8X-RAY DIFFRACTION6B161 - 173
9X-RAY DIFFRACTION6B184 - 193
10X-RAY DIFFRACTION7B174 - 183
11X-RAY DIFFRACTION8B94 - 160
12X-RAY DIFFRACTION8B195 - 291
13X-RAY DIFFRACTION9C5 - 93
14X-RAY DIFFRACTION10C161 - 173
15X-RAY DIFFRACTION10C184 - 193
16X-RAY DIFFRACTION11C174 - 183
17X-RAY DIFFRACTION12C94 - 160
18X-RAY DIFFRACTION12C195 - 293
19X-RAY DIFFRACTION13D6 - 93
20X-RAY DIFFRACTION14D161 - 173
21X-RAY DIFFRACTION14D184 - 193
22X-RAY DIFFRACTION15D174 - 183
23X-RAY DIFFRACTION16D94 - 160
24X-RAY DIFFRACTION16D195 - 294

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