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- PDB-8xn7: Crystal structure of HPK1 kinase domain T165E,S171E phosphomimeti... -

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Basic information

Entry
Database: PDB / ID: 8xn7
TitleCrystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with compound 9f
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / Kinase
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
: / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsHuang, W.X. / Liu, R. / Ding, K.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32071446 China
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: Discovery of 5-aminopyrido[2,3-d]pyrimidin-7(8H)-one derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors.
Authors: Qiu, X. / Liu, R. / Ling, H. / Zhou, Y. / Ren, X. / Zhou, F. / Zhang, J. / Huang, W. / Wang, Z. / Ding, K.
History
DepositionDec 29, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 10, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)67,3224
Polymers66,3012
Non-polymers1,0212
Water97354
1
A: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6612
Polymers33,1501
Non-polymers5111
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)33,6612
Polymers33,1501
Non-polymers5111
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.865, 76.997, 89.754
Angle α, β, γ (deg.)90.000, 93.910, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1(chain "B" and (resid 6 through 292 or resid 301))

NCS oper: (Code: givenMatrix: (0.527270595902, 0.0862666476516, 0.845306917161), (0.119146788445, -0.992510282727, 0.0269700108263), (0.841302419764, 0.0864951107503, -0.53359988223)Vector: 26. ...NCS oper: (Code: given
Matrix: (0.527270595902, 0.0862666476516, 0.845306917161), (0.119146788445, -0.992510282727, 0.0269700108263), (0.841302419764, 0.0864951107503, -0.53359988223)
Vector: 26.8331356375, -36.2828332354, -44.1731968598)

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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: 33150.496 Da / Num. of mol.: 2 / Mutation: T165E,S171E
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-A1LVT / 5-amino-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one


Mass: 510.511 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H25F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 54 / 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: 2.45 Å3/Da / Density % sol: 49.72 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M sodium chloride, 0.1 M Tris, 8%(w/v)PEG 20000, pH=8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NFPSS / Beamline: BL17B / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Mar 25, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.65→44.77 Å / Num. obs: 17275 / % possible obs: 94.8 % / Redundancy: 6.4 % / Biso Wilson estimate: 40.04 Å2 / CC1/2: 0.999 / Net I/σ(I): 22.9
Reflection shellResolution: 2.65→2.78 Å / Num. unique obs: 1750 / CC1/2: 0.965

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6NFY

6nfy


Resolution: 2.65→44.77 Å / SU ML: 0.3053 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 26.8028
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2302 1724 10 %
Rwork0.2144 15516 -
obs0.2159 17240 94.49 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.62 Å2
Refinement stepCycle: LAST / Resolution: 2.65→44.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4544 0 74 54 4672
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084724
X-RAY DIFFRACTIONf_angle_d0.90936395
X-RAY DIFFRACTIONf_chiral_restr0.0645701
X-RAY DIFFRACTIONf_plane_restr0.0064798
X-RAY DIFFRACTIONf_dihedral_angle_d16.75741763
Refine LS restraints NCSType: Torsion NCS / Rms dev position: 0.901806539852 Å
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.65-2.730.28931030.3002955X-RAY DIFFRACTION69.51
2.73-2.820.35371280.29511118X-RAY DIFFRACTION83.79
2.82-2.920.30881400.2771262X-RAY DIFFRACTION92.72
2.92-3.030.29811490.27611299X-RAY DIFFRACTION95.33
3.03-3.170.29581380.28061330X-RAY DIFFRACTION98.33
3.17-3.340.32051480.26961366X-RAY DIFFRACTION99.02
3.34-3.550.251570.24291354X-RAY DIFFRACTION99.34
3.55-3.820.23331540.21391362X-RAY DIFFRACTION99.28
3.82-4.210.1961500.18471344X-RAY DIFFRACTION99.67
4.21-4.810.17511550.16631364X-RAY DIFFRACTION99.54
4.81-6.060.16881460.18061376X-RAY DIFFRACTION99.48
6.06-44.770.19131560.16911386X-RAY DIFFRACTION97.66
Refinement TLS params.Method: refined / Origin x: 13.7578875182 Å / Origin y: -18.0339654619 Å / Origin z: -21.8932628476 Å
111213212223313233
T0.31253406365 Å20.000892252192434 Å20.0394520235047 Å2-0.235702562463 Å20.0242232376113 Å2--0.235205598872 Å2
L0.580020429789 °2-0.409799702482 °2-0.453573641411 °2-1.2747565631 °20.525585512337 °2--0.804339411199 °2
S0.00188007854075 Å °0.0342958457936 Å °0.0297122562897 Å °-0.100177793763 Å °0.0222161963261 Å °-0.0786207447072 Å °0.0749414781311 Å °0.0303982274296 Å °-0.029486819429 Å °
Refinement TLS groupSelection details: all

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