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- PDB-7l24: HPK1 IN COMPLEX WITH COMPOUND 11 -

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Basic information

Entry
Database: PDB / ID: 7l24
TitleHPK1 IN COMPLEX WITH COMPOUND 11
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / HPK1 HEMATOPOIETIC PROGENITOR KINASE / 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 / protein phosphorylation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / cell population proliferation / protein phosphorylation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction / 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-XHV / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 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 1.2Mar 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)131,0138
Polymers129,3434
Non-polymers1,6704
Water1,22568
1
A: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7532
Polymers32,3361
Non-polymers4171
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)32,7532
Polymers32,3361
Non-polymers4171
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7532
Polymers32,3361
Non-polymers4171
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,7532
Polymers32,3361
Non-polymers4171
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)77.874, 107.669, 85.971
Angle α, β, γ (deg.)90.000, 107.980, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASPASPASNASNAA7 - 2931 - 287
21ASPASPASNASNBB7 - 2931 - 287
12ILEILEASNASNAA8 - 2932 - 287
22ILEILEASNASNCC8 - 2932 - 287
13ILEILELYSLYSAA8 - 2922 - 286
23ILEILELYSLYSDD8 - 2922 - 286
14ILEILEASNASNBB8 - 2932 - 287
24ILEILEASNASNCC8 - 2932 - 287
15ILEILELYSLYSBB8 - 2922 - 286
25ILEILELYSLYSDD8 - 2922 - 286
16ILEILELYSLYSCC8 - 2922 - 286
26ILEILELYSLYSDD8 - 2922 - 286

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 / MEKKK 1


Mass: 32335.705 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-XHV / 6-(2-fluoro-6-methoxyphenyl)-1-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-c]pyridine


Mass: 417.479 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H24FN5O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / 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: 2.65 Å3/Da / Density % sol: 53.69 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: UNDISCLOSED

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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: Oct 24, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 2.68→81.77 Å / Num. obs: 37113 / % possible obs: 97.6 % / Redundancy: 2.4 % / Biso Wilson estimate: 69.639 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.049 / Rsym value: 0.038 / Χ2: 0.997 / Net I/σ(I): 18.54
Reflection shellResolution: 2.68→2.93 Å / Redundancy: 2.4 % / Mean I/σ(I) obs: 69.49 / Num. unique obs: 8686 / CC1/2: 1 / Rrim(I) all: 0.561 / Rsym value: 0.438 / % possible all: 98

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PREVIOUSLY SOLVED STUCTURE

Resolution: 2.68→81.77 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.908 / SU B: 37.69 / SU ML: 0.355 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.075 / ESU R Free: 0.356 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.272 790 2.1 %RANDOM
Rwork0.2257 ---
obs0.2267 36323 97.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 215.03 Å2 / Biso mean: 82.986 Å2 / Biso min: 37.66 Å2
Baniso -1Baniso -2Baniso -3
1--3.05 Å20 Å2-0.24 Å2
2--3.23 Å20 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 2.68→81.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8789 0 124 69 8982
Biso mean--83.56 64.94 -
Num. residues----1111
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0198512
X-RAY DIFFRACTIONr_bond_other_d0.0030.028034
X-RAY DIFFRACTIONr_angle_refined_deg1.3621.9811610
X-RAY DIFFRACTIONr_angle_other_deg2.141318288
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.18251100
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.11324.116328
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.32615.0931291
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.3651532
X-RAY DIFFRACTIONr_chiral_restr0.0710.21335
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219721
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021875
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A88190.07
12B88190.07
21A88370.08
22C88370.08
31A84660.08
32D84660.08
41B86010.07
42C86010.07
51B82790.08
52D82790.08
61C82190.08
62D82190.08
LS refinement shellResolution: 2.68→2.75 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 53 -
Rwork0.344 2678 -
all-2731 -
obs--97.68 %
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)
13.03540.5695-0.9527.7928-0.28114.1809-0.1885-0.576-0.8990.37570.11530.24270.8321-0.14380.07330.6577-0.0784-0.01240.56720.060.5059-57.5486.73424.357
24.4729-2.0424-3.61410.98081.15418.3156-0.0267-0.0257-0.5935-0.0350.03720.29170.4988-0.198-0.01050.7572-0.12350.23720.87330.01810.4463-62.94222.83649.764
34.73320.58680.21764.66620.48834.14330.2608-0.3030.25250.1156-0.0391-0.1645-0.26330.1084-0.22160.4539-0.0410.12790.3464-0.02210.0582-44.30729.49128.576
40.6092-2.5726-0.650610.98762.86591.2347-0.1447-0.00370.01440.4560.2424-0.08820.22030.1735-0.09770.65360.1189-0.02421.03950.02290.2885-7.303-17.00630.603
57.19222.7384-3.9381.84-3.28026.2361-0.30780.0384-0.7473-0.22670.0237-0.20750.62560.1130.28410.71810.02480.18490.6417-0.08050.19875.3014.4062.304
65.6118-0.9854-0.53814.4768-0.07032.7567-0.1113-0.5250.2376-0.07390.1354-0.0669-0.07720.2088-0.02420.39890.00420.04710.6179-0.10750.0298-16.7987.25124.33
71.24041.0481-0.41048.19112.73834.1016-0.04590.2354-0.36270.3150.0548-0.24040.68390.4873-0.0090.75280.14240.02670.6529-0.02130.4721-37.6693.522-9.792
82.88951.5856-4.72840.9083-2.954611.7837-0.1492-0.2073-1.0481-0.0476-0.1176-0.42890.57250.56980.26680.7637-0.0670.12240.98780.01460.9482-22.58521.271-32.428
94.20740.2554-1.19043.9003-0.63266.09820.11450.30970.4056-0.13150.0138-0.0472-0.63910.1696-0.12820.575-0.08580.06790.4403-0.02710.052-42.37329.382-11.819
100.466-0.57110.892310.4742-2.69942.31790.1706-0.1011-0.52280.28510.57560.41130.6715-0.0568-0.74621.1050.05460.19651.4153-0.33360.9924-77.67-16.943-20
117.059-2.4428-3.74090.86861.03775.7231-0.3396-0.0139-0.90090.02850.03840.30350.72720.10440.30110.6935-0.11880.23710.6964-0.08450.2056-87.754-0.2765.651
125.54461.64391.02313.7436-0.02773.4719-0.40320.9383-0.2038-0.0090.3924-0.21280.21050.22390.01090.5614-0.18040.14750.9552-0.14880.059-70.3828.844-16.386
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A7 - 93
2X-RAY DIFFRACTION2A161 - 193
3X-RAY DIFFRACTION3A94 - 160
4X-RAY DIFFRACTION3A195 - 293
5X-RAY DIFFRACTION4B7 - 93
6X-RAY DIFFRACTION5B161 - 193
7X-RAY DIFFRACTION6B94 - 160
8X-RAY DIFFRACTION6B195 - 293
9X-RAY DIFFRACTION7C8 - 93
10X-RAY DIFFRACTION8C161 - 193
11X-RAY DIFFRACTION9C94 - 160
12X-RAY DIFFRACTION9C195 - 293
13X-RAY DIFFRACTION10D8 - 93
14X-RAY DIFFRACTION11D161 - 193
15X-RAY DIFFRACTION12D94 - 160
16X-RAY DIFFRACTION12D195 - 292

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