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- PDB-7rj8: CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED ... -

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Basic information

Entry
Database: PDB / ID: 7rj8
TitleCRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED WITH LIGAND (2R)-2-AMINO-N-[3-(DIFLUOROM ETHOXY)-4-(1,3-OXAZOL-5-YL)PHENYL]-4-METHYLPENTANAMIDE
ComponentsAP2-associated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE / AAK1 / LIGAND / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


presynaptic endocytosis / regulation of clathrin-dependent endocytosis / clathrin complex / AP-2 adaptor complex binding / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / Notch binding / clathrin-coated vesicle / positive regulation of Notch signaling pathway / cell leading edge ...presynaptic endocytosis / regulation of clathrin-dependent endocytosis / clathrin complex / AP-2 adaptor complex binding / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / Notch binding / clathrin-coated vesicle / positive regulation of Notch signaling pathway / cell leading edge / calyx of Held / clathrin-coated pit / terminal bouton / regulation of protein localization / presynapse / protein stabilization / non-specific serine/threonine protein kinase / protein phosphorylation / protein serine kinase activity / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / ATP binding / plasma membrane / cytosol
Similarity search - Function
Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-5QI / Chem-PG6 / Chem-YFV / AP2-associated protein kinase 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 Å
AuthorsPokross, M. / Muckelbauer, J.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.
Authors: Hartz, R.A. / Ahuja, V.T. / Nara, S.J. / Kumar, C.M.V. / Manepalli, R.K.V.L.P. / Sarvasiddhi, S.K. / Honkhambe, S. / Patankar, V. / Dasgupta, B. / Rajamani, R. / Muckelbauer, J.K. / Camac, D. ...Authors: Hartz, R.A. / Ahuja, V.T. / Nara, S.J. / Kumar, C.M.V. / Manepalli, R.K.V.L.P. / Sarvasiddhi, S.K. / Honkhambe, S. / Patankar, V. / Dasgupta, B. / Rajamani, R. / Muckelbauer, J.K. / Camac, D.M. / Ghosh, K. / Pokross, M. / Kiefer, S.E. / Brown, J.M. / Hunihan, L. / Gulianello, M. / Lewis, M. / Lippy, J.S. / Surti, N. / Hamman, B.D. / Allen, J. / Kostich, W.A. / Bronson, J.J. / Macor, J.E. / Dzierba, C.D.
History
DepositionJul 20, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 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 1.2Apr 3, 2024Group: 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: AP2-associated protein kinase 1
B: AP2-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,85312
Polymers71,9562
Non-polymers1,89710
Water5,098283
1
A: AP2-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8726
Polymers35,9781
Non-polymers8945
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: AP2-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9816
Polymers35,9781
Non-polymers1,0035
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.570, 74.570, 316.760
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein AP2-associated protein kinase 1 / Adaptor-associated kinase 1


Mass: 35978.223 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Aak1, Kiaa1048 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q3UHJ0, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 293 molecules

#2: Chemical ChemComp-5QI / N-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-D-leucinamide


Mass: 339.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H19F2N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PG6 / 1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE / Polyethylene glycol


Mass: 266.331 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H26O6
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-YFV / 5-[(4-aminopiperidin-1-yl)methyl]-N-{3-[5-(propan-2-yl)-1,3,4-thiadiazol-2-yl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine


Mass: 448.587 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28N8S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 283 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.06 Å3/Da / Density % sol: 59.8 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.9 M ammonium sulfate, 0.14 M sodium chloride, 0.1 M Bis-Tris pH 5.5, and 1% PEG 3350

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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: Nov 20, 2014 / Details: Kirkpatrick-Baez Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.59→48.28 Å / Num. obs: 29229 / % possible obs: 100 % / Redundancy: 12.5 % / Biso Wilson estimate: 68.77 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.094 / Rpim(I) all: 0.029 / Rrim(I) all: 0.101 / Net I/σ(I): 19 / Num. measured all: 365751
Reflection shellResolution: 2.59→3.18 Å / Redundancy: 13 % / Rmerge(I) obs: 0.321 / Mean I/σ(I) obs: 7.1 / Num. unique obs: 12983 / % possible all: 100

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Processing

Software
NameVersionClassification
Aimless0.3.5data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In house model

Resolution: 2.59→48.28 Å / Cor.coef. Fo:Fc: 0.9347 / Cor.coef. Fo:Fc free: 0.902 / SU R Cruickshank DPI: 0.362 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.411 / SU Rfree Blow DPI: 0.244 / SU Rfree Cruickshank DPI: 0.237
RfactorNum. reflection% reflectionSelection details
Rfree0.2218 1434 4.94 %RANDOM
Rwork0.1853 ---
obs0.1871 29007 99.99 %-
Displacement parametersBiso max: 165.55 Å2 / Biso mean: 55.27 Å2 / Biso min: 25.81 Å2
Baniso -1Baniso -2Baniso -3
1--0.3367 Å20 Å20 Å2
2---0.3367 Å20 Å2
3---0.6734 Å2
Refine analyzeLuzzati coordinate error obs: 0.293 Å
Refinement stepCycle: final / Resolution: 2.59→48.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4572 0 174 283 5029
Biso mean--73.48 55.47 -
Num. residues----602
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1629SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes117HARMONIC2
X-RAY DIFFRACTIONt_gen_planes752HARMONIC5
X-RAY DIFFRACTIONt_it4890HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion627SEMIHARMONIC5
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_contact5700SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4890HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6732HARMONIC21.24
X-RAY DIFFRACTIONt_omega_torsion2.97
X-RAY DIFFRACTIONt_other_torsion18.61
LS refinement shellResolution: 2.59→2.68 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3105 135 4.88 %
Rwork0.2123 2631 -
all0.2171 2766 -
obs--99.99 %

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