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- PDB-9d00: HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex w... -

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Basic information

Entry
Database: PDB / ID: 9d00
TitleHPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with compound 53
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / Kinase / 3D domain swap / inactive state
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 / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity ...MAP kinase kinase kinase kinase activity / cellular response to phorbol 13-acetate 12-myristate / JNK cascade / peptidyl-serine phosphorylation / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / cell population proliferation / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / 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
: / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.951 Å
AuthorsJohnson, E. / McTigue, M. / Cronin, C.N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer.
Authors: Gallego, R.A. / Cho-Schultz, S. / Del Bel, M. / Dechert-Schmitt, A.M. / Donaldson, J.S. / He, M. / Jalaie, M. / Kania, R. / Matthews, J. / McTigue, M. / Tuttle, J.B. / Risley, H. / Zhou, D. ...Authors: Gallego, R.A. / Cho-Schultz, S. / Del Bel, M. / Dechert-Schmitt, A.M. / Donaldson, J.S. / He, M. / Jalaie, M. / Kania, R. / Matthews, J. / McTigue, M. / Tuttle, J.B. / Risley, H. / Zhou, D. / Zhou, R. / Ahmad, O.K. / Bernier, L. / Berritt, S. / Braganza, J. / Chen, Z. / Cianfrogna, J.A. / Collins, M. / Costa Jones, C. / Cronin, C.N. / Davis, C. / Dress, K. / Edwards, M. / Farrell, W. / France, S.P. / Grable, N. / Johnson, E. / Johnson, T.W. / Jones, R. / Knauber, T. / Lafontaine, J. / Loach, R.P. / Maestre, M. / Miller, N. / Moen, M. / Monfette, S. / Morse, P. / Nager, A.R. / Niosi, M. / Richardson, P. / Rohner, A.K. / Sach, N.W. / Timofeevski, S. / Tucker, J.W. / Vetelino, B. / Zhang, L. / Nair, S.K.
History
DepositionAug 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 8, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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
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)139,6458
Polymers138,0204
Non-polymers1,6264
Water9,494527
1
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)69,8234
Polymers69,0102
Non-polymers8132
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5750 Å2
ΔGint-33 kcal/mol
Surface area25580 Å2
MethodPISA
2
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)69,8234
Polymers69,0102
Non-polymers8132
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5800 Å2
ΔGint-30 kcal/mol
Surface area25690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.780, 80.330, 84.090
Angle α, β, γ (deg.)103.45, 106.49, 103.18
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 / MEKKK 1


Mass: 34504.887 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-A1A1A / 4-[(1R)-1-aminopropyl]-6-methoxy-2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one


Mass: 406.481 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H26N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 527 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.46 Å3/Da / Density % sol: 49.99 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion, sitting drop
Details: Well Ingredients: Buffer: 0.1 M (2.5 uL of stock 1.0 M) Tris (pH 8.00) Salt: 0.01 M (0.5 uL of stock 0.5 M) Magnesium sulfate hydrate Precipitant: 21.0 %w/v (7.3943661972 uL of stock 71.0 ...Details: Well Ingredients: Buffer: 0.1 M (2.5 uL of stock 1.0 M) Tris (pH 8.00) Salt: 0.01 M (0.5 uL of stock 0.5 M) Magnesium sulfate hydrate Precipitant: 21.0 %w/v (7.3943661972 uL of stock 71.0 %w/v) 1,6 hexanediol Additive: 0.036 M (9.0 uL of stock 0.1 M) Barium Acetate Plate setup temperature: 13 C Plate incubation temperature: 13 C Drop volume from well: 0.3 uL Drop protein volume: 0.2 uL Protein concentration 15mg/ml

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Data collection

DiffractionMean temperature: 95 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Feb 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→76.43 Å / Num. obs: 66808 / % possible obs: 84.5 % / Redundancy: 3.5 % / CC1/2: 0.996 / Net I/σ(I): 10
Reflection shellResolution: 1.95→2.11 Å / Num. unique obs: 3340 / CC1/2: 0.555

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (21-NOV-2022)refinement
XDSdata reduction
STARANISOdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.951→33.34 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.922 / SU R Cruickshank DPI: 0.315 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.307 / SU Rfree Blow DPI: 0.228 / SU Rfree Cruickshank DPI: 0.233
RfactorNum. reflection% reflectionSelection details
Rfree0.2791 3298 4.94 %RANDOM
Rwork0.2457 ---
obs0.2474 66792 69.8 %-
Displacement parametersBiso mean: 57.29 Å2
Baniso -1Baniso -2Baniso -3
1--3.6006 Å2-4.108 Å2-0.7852 Å2
2--4.8049 Å21.6708 Å2
3----1.2043 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: LAST / Resolution: 1.951→33.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8985 0 120 528 9633
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0089303HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9112577HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3254SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1556HARMONIC5
X-RAY DIFFRACTIONt_it9303HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.83
X-RAY DIFFRACTIONt_other_torsion17.49
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1166SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7478SEMIHARMONIC4
LS refinement shellResolution: 1.951→2.06 Å
RfactorNum. reflection% reflection
Rfree0.3584 -6.66 %
Rwork0.3058 1247 -
obs--9.51 %
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)
10.2616-0.08920.16540.1487-0.71882.32310.0339-0.0041-0.0199-0.0375-0.06060.0893-0.05150.2380.0267-0.063-0.0609-0.00580.09660.0341-0.066554.9909-47.1589-36.8234
21.1674-0.27270.2834-0.0726-0.31521.2139-0.01030.01910.03120.03850.028-0.00570.0051-0.0795-0.0178-0.0932-0.047-0.00760.04150.01790.008140.3957-33.055-73.0147
31.51292.03770.14834.8721-0.36060.14140.16480.20370.04040.75690.0239-0.0271-0.058-0.0395-0.18870.0609-0.0995-0.0009-0.0911-0.0089-0.081133.0252-19.4722-0.4664
40.30760.25580.18051.8728-1.46362.03160.0526-0.0231-0.0574-0.6527-0.21420.07740.3988-0.0950.16160.20130.0178-0.0585-0.0662-0.0687-0.154518.2932-5.1795-36.7186
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }

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