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- PDB-7siu: Crystal structure of HPK1 (MAP4K1) complex with inhibitor A-745 -

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Basic information

Entry
Database: PDB / ID: 7siu
TitleCrystal structure of HPK1 (MAP4K1) complex with inhibitor A-745
ComponentsMitogen-activated protein kinase kinase kinase kinase 1
KeywordsSIGNALING PROTEIN / Transferase / Protein 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-9ID / Mitogen-activated protein kinase kinase kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.786 Å
AuthorsLongenecker, K.L. / Korepanova, A. / Qiu, W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Chem.Biol. / Year: 2022
Title: The HPK1 Inhibitor A-745 Verifies the Potential of Modulating T Cell Kinase Signaling for Immunotherapy.
Authors: Malchow, S. / Korepanova, A. / Panchal, S.C. / McClure, R.A. / Longenecker, K.L. / Qiu, W. / Zhao, H. / Cheng, M. / Guo, J. / Klinge, K.L. / Trusk, P. / Pratt, S.D. / Li, T. / Kurnick, M.D. ...Authors: Malchow, S. / Korepanova, A. / Panchal, S.C. / McClure, R.A. / Longenecker, K.L. / Qiu, W. / Zhao, H. / Cheng, M. / Guo, J. / Klinge, K.L. / Trusk, P. / Pratt, S.D. / Li, T. / Kurnick, M.D. / Duan, L. / Shoemaker, A.R. / Gopalakrishnan, S.M. / Warder, S.E. / Shotwell, J.B. / Lai, A. / Sun, C. / Osuma, A.T. / Pappano, W.N.
History
DepositionOct 14, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2022Group: 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 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)70,3195
Polymers69,3882
Non-polymers9313
Water12,683704
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5770 Å2
ΔGint-59 kcal/mol
Surface area27150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.370, 69.370, 323.590
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 34693.980 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP4K1, HPK1 / Cell line (production host): HEK (293-6E) / Production host: Homo sapiens (human)
References: UniProt: Q92918, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-9ID / 6-[(5R)-5-benzamidocyclohex-1-en-1-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide


Mass: 417.464 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H23N7O2 / 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.: 704 / 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: 2.81 Å3/Da / Density % sol: 56.15 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 20% PEG1000, 100 mM Li2SO4, 100 mM Sodium Citrate, pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.786→80.9 Å / Num. obs: 75564 / % possible obs: 98.9 % / Redundancy: 11 % / Biso Wilson estimate: 26.27 Å2 / Rpim(I) all: 0.029 / Net I/σ(I): 17.6
Reflection shellResolution: 1.787→1.817 Å / Num. unique obs: 3293 / Rpim(I) all: 0.405

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
BUSTER2.11.7 (19-MAR-2020)refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ggf

3ggf


Resolution: 1.786→80.9 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.94 / SU R Cruickshank DPI: 0.104 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.115 / SU Rfree Blow DPI: 0.104 / SU Rfree Cruickshank DPI: 0.097
RfactorNum. reflection% reflectionSelection details
Rfree0.2054 3744 4.95 %RANDOM
Rwork0.1857 ---
obs0.1867 75564 98.8 %-
Displacement parametersBiso max: 88.65 Å2 / Biso mean: 29.2 Å2 / Biso min: 12.95 Å2
Baniso -1Baniso -2Baniso -3
1--1.7366 Å20 Å20 Å2
2---1.7366 Å20 Å2
3---3.4732 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: final / Resolution: 1.786→80.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4541 0 67 704 5312
Biso mean--27.31 42.28 -
Num. residues----579
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1639SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes825HARMONIC5
X-RAY DIFFRACTIONt_it4712HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion596SEMIHARMONIC5
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_contact4630SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4712HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6382HARMONIC20.88
X-RAY DIFFRACTIONt_omega_torsion3.3
X-RAY DIFFRACTIONt_other_torsion15.04
LS refinement shellResolution: 1.79→1.8 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2476 81 5.36 %
Rwork0.2347 1431 -
all0.2354 1512 -
obs--85.77 %

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