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

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Basic information

Entry
Database: PDB / ID: 8fko
TitleCrystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with 3-{4-[(2S,5R)-5-Amino-2-methylpiperidin-1-yl]-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE/INHIBITOR / inhibitor / hematopoietic / kinase / 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 / 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-Y3O / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.104 Å
AuthorsMcTigue, M. / Johnson, E. / Cronin, C.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2023
Title: Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.
Authors: Gallego, R.A. / Bernier, L. / Chen, H. / Cho-Schultz, S. / Chung, L. / Collins, M. / Del Bel, M. / Elleraas, J. / Costa Jones, C. / Cronin, C.N. / Edwards, M. / Fang, X. / Fisher, T. / He, M. ...Authors: Gallego, R.A. / Bernier, L. / Chen, H. / Cho-Schultz, S. / Chung, L. / Collins, M. / Del Bel, M. / Elleraas, J. / Costa Jones, C. / Cronin, C.N. / Edwards, M. / Fang, X. / Fisher, T. / He, M. / Hoffman, J. / Huo, R. / Jalaie, M. / Johnson, E. / Johnson, T.W. / Kania, R.S. / Kraus, M. / Lafontaine, J. / Le, P. / Liu, T. / Maestre, M. / Matthews, J. / McTigue, M. / Miller, N. / Mu, Q. / Qin, X. / Ren, S. / Richardson, P. / Rohner, A. / Sach, N. / Shao, L. / Smith, G. / Su, R. / Sun, B. / Timofeevski, S. / Tran, P. / Wang, S. / Wang, W. / Zhou, R. / Zhu, J. / Nair, S.K.
History
DepositionDec 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 5, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _pdbx_initial_refinement_model.details

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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
E: Mitogen-activated protein kinase kinase kinase kinase 1
F: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)224,68411
Polymers222,8506
Non-polymers1,8345
Water13,205733
1
A: Mitogen-activated protein kinase kinase kinase kinase 1
C: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,0174
Polymers74,2832
Non-polymers7342
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3940 Å2
ΔGint-32 kcal/mol
Surface area26280 Å2
MethodPISA
2
B: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules

F: Mitogen-activated protein kinase kinase kinase kinase 1


Theoretical massNumber of molelcules
Total (without water)74,6503
Polymers74,2832
Non-polymers3671
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_545x,y-1,z1
Buried area3810 Å2
ΔGint-31 kcal/mol
Surface area22770 Å2
MethodPISA
3
D: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules

E: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,0174
Polymers74,2832
Non-polymers7342
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_545x,y-1,z1
Buried area3740 Å2
ΔGint-30 kcal/mol
Surface area25390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.074, 86.996, 109.817
Angle α, β, γ (deg.)95.73, 100.64, 108.89
Int Tables number1
Space group name H-MP1

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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: 37141.656 Da / Num. of mol.: 6 / Mutation: S165E, T171E
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-Y3O / (3P)-3-{4-[(2S,5R)-5-amino-2-methylpiperidin-1-yl]-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile


Mass: 366.847 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C19H19ClN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 733 / 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: 2.28 Å3/Da / Density % sol: 46.07 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion, sitting drop
Details: 15 mg/mL protein + reservoir (0.1 M Tris, pH 8.0, 17.5% 1,6-hexanediol, 10 mM magnesium sulfate, 24 mM barium acetate)

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Data collection

DiffractionMean temperature: 180 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→52.91 Å / Num. obs: 110855 / % possible obs: 97 % / Redundancy: 3.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.055 / Net I/σ(I): 11.7
Reflection shellResolution: 2.1→2.22 Å / Rmerge(I) obs: 0.496 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 16208 / CC1/2: 0.774 / % possible all: 96.7

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6NG0

6ng0


Resolution: 2.104→52.91 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.909 / SU R Cruickshank DPI: 0.228 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.223 / SU Rfree Blow DPI: 0.187 / SU Rfree Cruickshank DPI: 0.191
RfactorNum. reflection% reflectionSelection details
Rfree0.258 5556 -RANDOM
Rwork0.2199 ---
obs0.2218 110840 97 %-
Displacement parametersBiso mean: 46.43 Å2
Baniso -1Baniso -2Baniso -3
1-2.787 Å2-5.0137 Å22.8736 Å2
2--3.0805 Å21.4435 Å2
3----5.8675 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: LAST / Resolution: 2.104→52.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12683 0 130 733 13546
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00813095HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9117743HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4524SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2274HARMONIC5
X-RAY DIFFRACTIONt_it13095HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1683SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact10834SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.75
X-RAY DIFFRACTIONt_other_torsion17.6
LS refinement shellResolution: 2.104→2.12 Å
RfactorNum. reflection% reflection
Rfree0.339 114 -
Rwork0.2904 --
obs--92.82 %

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