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

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Basic information

Entry
Database: PDB / ID: 7lvh
TitleCRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED WITH LIGAND N-[3-METHOXY-4-(1,3-OXAZOL-5-YL)PHENYL]-3-(PROPAN-2-YL)PIPERIDINE-2-CARBOXAMIDE
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-YFS / Chem-YFV / AP2-associated protein kinase 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsMuckelbauer, J.K.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery, Structure-Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain.
Authors: Hartz, R.A. / Ahuja, V.T. / Nara, S.J. / Kumar, C.M.V. / Brown, J.M. / Bristow, L.J. / Rajamani, R. / Muckelbauer, J.K. / Camac, D. / Kiefer, S.E. / Hunihan, L. / Gulianello, M. / Lewis, M. ...Authors: Hartz, R.A. / Ahuja, V.T. / Nara, S.J. / Kumar, C.M.V. / Brown, J.M. / Bristow, L.J. / Rajamani, R. / Muckelbauer, J.K. / Camac, D. / Kiefer, S.E. / Hunihan, L. / Gulianello, M. / Lewis, M. / Easton, A. / Lippy, J.S. / Surti, N. / Pattipati, S.N. / Dokania, M. / Elavazhagan, S. / Dandapani, K. / Hamman, B.D. / Allen, J. / Kostich, W. / Bronson, J.J. / Macor, J.E. / Dzierba, C.D.
History
DepositionFeb 25, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 28, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 4, 2021Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID
Revision 1.2Aug 11, 2021Group: Database references / Category: database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Aug 25, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Apr 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)72,9016
Polymers71,9562
Non-polymers9444
Water19811
1
A: AP2-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3783
Polymers35,9781
Non-polymers3992
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)36,5233
Polymers35,9781
Non-polymers5452
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)91.514, 91.514, 172.145
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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


Mass: 303.356 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H21N3O3
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: 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
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 2.89 Å3/Da / Density % sol: 57.47 %
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: ADSC QUANTUM 210 / Detector: CCD / Date: Dec 18, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.65→46.48 Å / Num. obs: 24933 / % possible obs: 100 % / Redundancy: 10.7 % / Biso Wilson estimate: 76.94 Å2 / Rrim(I) all: 0.097 / Rsym value: 0.092 / Χ2: 0.95 / Net I/σ(I): 10.9
Reflection shellResolution: 2.65→2.74 Å / Redundancy: 11 % / Mean I/σ(I) obs: 3.3 / Num. unique obs: 2458 / Rsym value: 0.514 / % possible all: 100

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Processing

Software
NameVersionClassification
d*TREKdata reduction
d*TREK9.9.3Ldata scaling
BUSTER2.11.5refinement
PDB_EXTRACT3.27data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: in-house model

Resolution: 2.65→30.67 Å / Cor.coef. Fo:Fc: 0.9024 / Cor.coef. Fo:Fc free: 0.8752 / SU R Cruickshank DPI: 0.52 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.507 / SU Rfree Blow DPI: 0.321 / SU Rfree Cruickshank DPI: 0.326
RfactorNum. reflection% reflectionSelection details
Rfree0.2988 1267 5.09 %RANDOM
Rwork0.265 ---
obs0.2668 24905 99.95 %-
Displacement parametersBiso max: 138.8 Å2 / Biso mean: 59.96 Å2 / Biso min: 30.19 Å2
Baniso -1Baniso -2Baniso -3
1-2.5942 Å20 Å20 Å2
2--2.5942 Å20 Å2
3----5.1885 Å2
Refine analyzeLuzzati coordinate error obs: 0.488 Å
Refinement stepCycle: final / Resolution: 2.65→30.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4181 0 113 11 4305
Biso mean--55.57 48.05 -
Num. residues----565
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1391SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes95HARMONIC2
X-RAY DIFFRACTIONt_gen_planes688HARMONIC5
X-RAY DIFFRACTIONt_it4372HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion590SEMIHARMONIC5
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_contact4728SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4372HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5986HARMONIC21.17
X-RAY DIFFRACTIONt_omega_torsion2.85
X-RAY DIFFRACTIONt_other_torsion19.23
LS refinement shellResolution: 2.65→2.76 Å / Rfactor Rfree error: 0 / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.3472 116 4.2 %
Rwork0.2679 2647 -
all0.2714 2763 -
obs--99.95 %

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