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- PDB-8cij: CRYSTAL STRUCTURE OF HUMAN HPK1 (MAP4K1) COMPLEX WITH 2-[8-Amino-... -

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Basic information

Entry
Database: PDB / ID: 8cij
TitleCRYSTAL STRUCTURE OF HUMAN HPK1 (MAP4K1) COMPLEX WITH 2-[8-Amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-isoquinolin-3-ylamino]-6-isopropyl-5,6-dihydro-4H-1,6,8a-triaza-azulen-7-one
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsTRANSFERASE / PROTEIN KINASE / SIGNALING PROTEIN / MAP4K1 / HEMATOPOIETIC PROGENITOR 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-USF / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.821 Å
AuthorsMusil, D. / Toure, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2023
Title: Discovery of quinazoline HPK1 inhibitors with high cellular potency.
Authors: Toure, M. / Johnson, T. / Li, B. / Schmidt, R. / Ma, H. / Neagu, C. / Lopez, A.U. / Wang, Y. / Guler, S. / Xiao, Y. / Henkes, R. / Ho, K. / Zhang, S. / Chu, C.L. / Gundra, U.M. / Porichis, F. ...Authors: Toure, M. / Johnson, T. / Li, B. / Schmidt, R. / Ma, H. / Neagu, C. / Lopez, A.U. / Wang, Y. / Guler, S. / Xiao, Y. / Henkes, R. / Ho, K. / Zhang, S. / Chu, C.L. / Gundra, U.M. / Porichis, F. / Li, L. / Maurer, C.K. / Fang, Z. / Musil, D. / DiPoto, M. / Friis, E. / Jones, R. / Jones, C. / Cummings, J. / Chekler, E. / Tanzer, E.M. / Huck, B. / Sherer, B.
History
DepositionFeb 9, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8772
Polymers34,3611
Non-polymers5171
Water1267
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.976, 75.976, 131.973
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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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: 34360.754 Da / Num. of mol.: 1
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-USF / 2-[[8-azanyl-7-fluoranyl-6-(8-methyl-2,3-dihydro-1~{H}-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl]amino]-6-propan-2-yl-5,8-dihydro-4~{H}-pyrazolo[1,5-d][1,4]diazepin-7-one / 2-[8-Amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-isoquinolin-3-ylamino]-6-isopropyl-5,6-dihydro-4H-1,6,8a-triaza-azulen-7-one


Mass: 516.570 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29FN8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 2.77 Å3/Da / Density % sol: 55.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 10 % PEG 4000, 120 mM NaCl, 01. M HEPES, pH = 7.75 / PH range: 7.75

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08B1-1 / Wavelength: 0.97957 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97957 Å / Relative weight: 1
ReflectionResolution: 2.821→65.844 Å / Num. obs: 8077 / % possible obs: 82.1 % / Redundancy: 15.6 % / CC1/2: 0.999 / Rpim(I) all: 0.053 / Net I/σ(I): 11.3
Reflection shellResolution: 2.821→3.027 Å / Num. unique obs: 404 / CC1/2: 0.5 / Rpim(I) all: 0.717

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Processing

Software
NameClassification
BUSTERrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.821→65.84 Å / Cor.coef. Fo:Fc: 0.908 / Cor.coef. Fo:Fc free: 0.953 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.411
RfactorNum. reflection% reflectionSelection details
Rfree0.266 388 4.8 %RANDOM
Rwork0.2373 ---
obs0.2388 8077 82 %-
Displacement parametersBiso mean: 97.68 Å2
Baniso -1Baniso -2Baniso -3
1--0.7476 Å20 Å20 Å2
2---0.7476 Å20 Å2
3---1.4952 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: 1 / Resolution: 2.821→65.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1988 0 38 7 2033
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0072181HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.912949HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d768SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes353HARMONIC5
X-RAY DIFFRACTIONt_it2181HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.36
X-RAY DIFFRACTIONt_other_torsion17.71
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion270SEMIHARMONIC5
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_contact1669SEMIHARMONIC4
LS refinement shellResolution: 2.821→3.03 Å
RfactorNum. reflection% reflection
Rfree0.3069 -4.46 %
Rwork0.3082 407 -
Refinement TLS params.Method: refined / Origin x: 14.88 Å / Origin y: 32.086 Å / Origin z: 6.5509 Å
111213212223313233
T0.0041 Å20.0539 Å20.0618 Å2--0.1915 Å20.0107 Å2---0.0849 Å2
L3.0096 °21.1281 °20.0088 °2-5.1254 °20.6817 °2--3.7953 °2
S0.0508 Å °0.3623 Å °0.2321 Å °-0.074 Å °-0.1317 Å °0.1282 Å °-0.1444 Å °-0.1728 Å °0.0808 Å °
Refinement TLS groupSelection details: { A|* }

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