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- PDB-8fh4: Crystal structure of HPK1 kinase domain T165E,S171E phosphomimeti... -

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Basic information

Entry
Database: PDB / ID: 8fh4
TitleCrystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with 3-[6-chloro-4-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undec-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / inhibitor / hematopoietic / 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 / 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. / Protein kinase domain profile. ...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-XXF / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.827 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 13, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,3549
Polymers148,5674
Non-polymers1,7885
Water15,025834
1
A: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,5652
Polymers37,1421
Non-polymers4231
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)37,6613
Polymers37,1421
Non-polymers5192
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)37,5652
Polymers37,1421
Non-polymers4231
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)37,5652
Polymers37,1421
Non-polymers4231
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.756, 70.505, 86.042
Angle α, β, γ (deg.)97.66, 108.73, 92.66
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.: 4 / 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-XXF / (3P)-3-[6-chloro-4-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile


Mass: 422.911 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H23ClN6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 834 / 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: 2.2 Å3/Da / Density % sol: 44.18 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion
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 PILATUS3 6M / Detector: PIXEL / Date: Mar 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.83→69.56 Å / Num. obs: 92890 / % possible obs: 82.6 % / Redundancy: 1.8 % / CC1/2: 0.996 / Rmerge(I) obs: 0.03 / Rpim(I) all: 0.03 / Rrim(I) all: 0.042 / Net I/σ(I): 9.7
Reflection shellResolution: 1.83→1.93 Å / Redundancy: 1.6 % / Rmerge(I) obs: 0.292 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 4111 / CC1/2: 0.833 / Rpim(I) all: 0.292 / % possible all: 25

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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: 1.827→69.56 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.939 / SU R Cruickshank DPI: 0.159 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.161 / SU Rfree Blow DPI: 0.137 / SU Rfree Cruickshank DPI: 0.138
RfactorNum. reflection% reflectionSelection details
Rfree0.2152 4440 -RANDOM
Rwork0.1874 ---
obs0.1888 92889 82.6 %-
Displacement parametersBiso mean: 31.69 Å2
Baniso -1Baniso -2Baniso -3
1-1.4506 Å20.1642 Å22.3978 Å2
2---4.8007 Å21.1515 Å2
3---3.3501 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: LAST / Resolution: 1.827→69.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9114 0 125 834 10073
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0089452HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9112790HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3354SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1639HARMONIC5
X-RAY DIFFRACTIONt_it9452HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1183SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact8592SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.99
X-RAY DIFFRACTIONt_other_torsion17.32
LS refinement shellResolution: 1.83→1.85 Å
RfactorNum. reflection% reflection
Rfree0.2615 99 -
Rwork0.2534 --
obs0.2539 1858 40.91 %

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