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- PDB-7l25: HPK1 IN COMPLEX WITH COMPOUND 18 -

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Basic information

Entry
Database: PDB / ID: 7l25
TitleHPK1 IN COMPLEX WITH COMPOUND 18
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE/TRANSFERASE inhibitor / HPK1 HEMATOPOIETIC PROGENITOR KINASE / INHIBITOR COMPLEX / 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. ...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-XHS / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsLesburg, C.A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2021
Title: Identification of Potent Reverse Indazole Inhibitors for HPK1.
Authors: Yu, E.C. / Methot, J.L. / Fradera, X. / Lesburg, C.A. / Lacey, B.M. / Siliphaivanh, P. / Liu, P. / Smith, D.M. / Xu, Z. / Piesvaux, J.A. / Kawamura, S. / Xu, H. / Miller, J.R. / Bittinger, M. / Pasternak, A.
History
DepositionDec 16, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 17, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 31, 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 1.2Apr 3, 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_initial_refinement_model / 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

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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)65,9518
Polymers64,8662
Non-polymers1,0856
Water7,098394
1
A: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9754
Polymers32,4331
Non-polymers5433
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9754
Polymers32,4331
Non-polymers5433
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.397, 97.729, 71.397
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: ASP / Beg label comp-ID: ASP / End auth comp-ID: LYS / End label comp-ID: LYS / Refine code: _ / Auth seq-ID: 7 - 292 / Label seq-ID: 2 - 287

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 / MEKKK 1


Mass: 32432.822 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q92918, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-XHS / 6-(2-fluoro-6-methoxyphenyl)-1-[6-(4-methylpiperazin-1-yl)pyridin-2-yl]-1H-pyrazolo[4,3-c]pyridine


Mass: 418.467 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23FN6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 394 / 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: 2.43 Å3/Da / Density % sol: 49.49 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: NO DISCLOSED

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 20, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 1.85→71.4 Å / Num. obs: 51003 / % possible obs: 93.2 % / Redundancy: 4.2 % / Biso Wilson estimate: 36.868 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.053 / Rsym value: 0.047 / Χ2: 1.003 / Net I/σ(I): 18.7
Reflection shellResolution: 1.85→2.1 Å / Redundancy: 2.4 % / Mean I/σ(I) obs: 2.18 / Num. unique obs: 13779 / CC1/2: 0.999 / Rrim(I) all: 0.549 / Rsym value: 0.437 / % possible all: 80.6

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Processing

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

Resolution: 1.85→71.4 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.943 / SU B: 7.439 / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.148 / ESU R Free: 0.139 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2266 2334 4.6 %RANDOM
Rwork0.1855 ---
obs0.1873 48669 93.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 121.36 Å2 / Biso mean: 39.405 Å2 / Biso min: 12.4 Å2
Baniso -1Baniso -2Baniso -3
1-0.28 Å20 Å20 Å2
2--0.76 Å2-0 Å2
3----1.04 Å2
Refinement stepCycle: final / Resolution: 1.85→71.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4544 0 82 394 5020
Biso mean--31.76 42.09 -
Num. residues----576
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0194667
X-RAY DIFFRACTIONr_bond_other_d0.0040.024527
X-RAY DIFFRACTIONr_angle_refined_deg1.6131.9876330
X-RAY DIFFRACTIONr_angle_other_deg1.287310362
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4925580
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.79823.368193
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.93215.076792
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2531528
X-RAY DIFFRACTIONr_chiral_restr0.10.2707
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0215237
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021059
Refine LS restraints NCS

Ens-ID: 1 / Number: 6842 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.03 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.85→1.898 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.371 131 -
Rwork0.366 2432 -
all-2563 -
obs--64.35 %
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)
13.1533-0.74141.71671.2325-0.62813.54220.2259-0.0414-0.7184-0.0344-0.05650.17440.6748-0.128-0.16950.24370.0017-0.00490.11310.01880.2665-18.0325.04-27.229
23.4492-2.1547-0.93233.483-0.06790.4565-0.12010.0008-0.59920.1172-0.04850.29180.0551-0.00520.16860.3119-0.0953-0.05290.1506-0.00520.211-40.9374.399-34.063
31.3913-0.2560.08091.76330.34362.746-0.0564-0.00960.12870.0786-0.0080.1683-0.1072-0.19090.06430.07450.0014-0.00410.01990.00360.0404-38.33821.183-37.897
42.2968-0.53570.55181.5381-1.76683.59340.0459-0.0232-0.03260.09590.09870.34-0.1459-0.4302-0.14460.22130.00070.00950.1344-0.04420.1977-39.7426.79-8.343
51.8642-2.097-0.01063.70580.35490.09790.01440.3644-0.2805-0.2338-0.12530.7432-0.03820.02080.11080.2207-0.1058-0.0080.37830.02020.2481-40.8734.268-1.196
61.757-0.1521-0.32181.34270.25332.2138-0.02690.1402-0.1875-0.0476-0.0407-0.10860.18280.13450.06770.086-0.0047-0.00780.05450.00390.0409-23.9036.3162.623
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A7 - 93
2X-RAY DIFFRACTION2A156 - 191
3X-RAY DIFFRACTION3A94 - 155
4X-RAY DIFFRACTION3A192 - 294
5X-RAY DIFFRACTION4B6 - 93
6X-RAY DIFFRACTION5B156 - 191
7X-RAY DIFFRACTION6B94 - 155
8X-RAY DIFFRACTION6B192 - 293

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