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

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Basic information

Entry
Database: PDB / ID: 8fjz
TitleCrystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with 3-{4-[(3R,5S)-3-Amino-5-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 / positive regulation of MAPK cascade / 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 / protein autophosphorylation / cell population proliferation / positive regulation of MAPK cascade / 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-Y3I / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.897 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 20, 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)225,05112
Polymers222,8506
Non-polymers2,2016
Water15,133840
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 area3890 Å2
ΔGint-30 kcal/mol
Surface area26190 Å2
MethodPISA
2
B: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules

F: 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 area3590 Å2
ΔGint-29 kcal/mol
Surface area25370 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 area3760 Å2
ΔGint-28 kcal/mol
Surface area25660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.71, 87.4, 109.071
Angle α, β, γ (deg.)96.43, 99.99, 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: 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-Y3I / (3P)-3-{4-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-6-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile


Mass: 366.847 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C19H19ClN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 840 / 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: 2.26 Å3/Da / Density % sol: 45.64 %
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: Nov 3, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→81.34 Å / Num. obs: 149381 / % possible obs: 96.5 % / Redundancy: 3.5 % / CC1/2: 0.996 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.04 / Net I/σ(I): 10.4
Reflection shellResolution: 1.9→2 Å / Rmerge(I) obs: 0.547 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 21930 / CC1/2: 0.841 / Rpim(I) all: 0.336

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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: 1.897→81.34 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.916 / SU R Cruickshank DPI: 0.161 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.158 / SU Rfree Blow DPI: 0.144 / SU Rfree Cruickshank DPI: 0.147
RfactorNum. reflection% reflectionSelection details
Rfree0.249 7448 -RANDOM
Rwork0.2145 ---
obs0.2162 149378 96.5 %-
Displacement parametersBiso mean: 44.21 Å2
Baniso -1Baniso -2Baniso -3
1-4.2878 Å2-6.236 Å25.1558 Å2
2--2.0776 Å23.4026 Å2
3----6.3654 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.897→81.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13174 0 156 840 14170
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00813620HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9218456HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d4716SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes2382HARMONIC5
X-RAY DIFFRACTIONt_it13620HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1751SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact11648SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.95
X-RAY DIFFRACTIONt_other_torsion16.4
LS refinement shellResolution: 1.9→1.91 Å
RfactorNum. reflection% reflection
Rfree0.3331 161 -
Rwork0.3 --
obs0.3019 2988 96.55 %

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