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- PDB-8cdw: CRYSTAL STRUCTURE OF HUMAN HPK1 (MAP4K1) COMPLEX WITH 7-(1-methyl... -

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Basic information

Entry
Database: PDB / ID: 8cdw
TitleCRYSTAL STRUCTURE OF HUMAN HPK1 (MAP4K1) COMPLEX WITH 7-(1-methyl-1H-pyrazol-4-yl)-N-[4-(1-methylpiperidin-4-yl)phenyl]quinazolin-2-amine
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 / 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-UES / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.941 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 1, 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
B: Mitogen-activated protein kinase kinase kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,5194
Polymers68,7222
Non-polymers7972
Water3,441191
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4520 Å2
ΔGint-37 kcal/mol
Surface area27190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.482, 76.676, 90.249
Angle α, β, γ (deg.)90.00, 96.48, 90.00
Int Tables number4
Space group name H-MP1211

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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.: 2
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-UES / ~{N}-[4-(1-methylpiperidin-4-yl)phenyl]-7-(1-methylpyrazol-4-yl)quinazolin-2-amine


Mass: 398.503 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H26N6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 191 / 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: 2.23 Å3/Da / Density % sol: 44.73 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 4.0 % (w/v) PEG5000 MME, 0.05 M HEPES, pH=6.50, 0.032 M Na3-Citrate, pH=7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9998 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 23, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9998 Å / Relative weight: 1
ReflectionResolution: 1.94→58.27 Å / Num. obs: 35094 / % possible obs: 78.7 % / Redundancy: 4.2 % / CC1/2: 0.992 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.053 / Net I/σ(I): 7.5
Reflection shellResolution: 1.94→2.01 Å / Mean I/σ(I) obs: 1.9 / Num. unique obs: 1755 / CC1/2: 0.73 / Rpim(I) all: 0.368

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Processing

Software
NameClassification
BUSTERrefinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.941→58.27 Å / SU R Cruickshank DPI: 0.255 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.249 / SU Rfree Blow DPI: 0.189 / SU Rfree Cruickshank DPI: 0.192
RfactorNum. reflection% reflectionSelection details
Rfree0.252 1801 5.13 %RANDOM
Rwork0.229 ---
obs-35094 78.7 %-
Displacement parametersBiso mean: 56 Å2
Baniso -1Baniso -2Baniso -3
1-2.7384 Å20 Å25.2689 Å2
2---3.2815 Å20 Å2
3---0.5432 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: LAST / Resolution: 1.941→58.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4355 0 60 191 4606
LS refinement shellResolution: 1.941→1.97 Å
RfactorNum. reflection% reflection
Rfree0.349 -4.99 %
Rwork0.288 667 -
obs--34.37 %

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