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- PDB-7rj7: CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED ... -

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Basic information

Entry
Database: PDB / ID: 7rj7
TitleCRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED WITH LIGAND 2-(1-AMINO-3-METHYLBUTYL)-6- (PYRIDIN-4-YL)QUINOLINE-4-CARBONITRILE
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-5P6 / AP2-associated protein kinase 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.124 Å
AuthorsMuckelbauer, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
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

Downloads & links

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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)73,16610
Polymers71,9562
Non-polymers1,2098
Water3,909217
1
A: AP2-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2952
Polymers35,9781
Non-polymers3161
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)36,8718
Polymers35,9781
Non-polymers8937
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)91.206, 91.206, 173.708
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-5P6 / 2-[(1S)-1-amino-3-methylbutyl]-6-(pyridin-4-yl)quinoline-4-carbonitrile


Mass: 316.400 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 2.92 Å3/Da / Density % sol: 57.94 %
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: Mar 2, 2011 / Details: ???
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.12→58.44 Å / Num. obs: 43896 / % possible obs: 92.7 % / Redundancy: 9.6 % / Biso Wilson estimate: 58.46 Å2 / Rmerge(I) obs: 0.058 / Net I/σ(I): 18.4
Reflection shellResolution: 2.12→2.21 Å / Redundancy: 10.5 % / Rmerge(I) obs: 1.387 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 2196 / % possible all: 48.7

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Processing

Software
NameVersionClassification
BUSTERrefinement
SCALA3.3.16data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: In house model

Resolution: 2.124→21.24 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.949 / SU R Cruickshank DPI: 0.459 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.232 / SU Rfree Blow DPI: 0.178 / SU Rfree Cruickshank DPI: 0.177
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2412 2237 5.1 %RANDOM
Rwork0.2288 ---
obs0.2295 43838 91.5 %-
Displacement parametersBiso max: 152.51 Å2 / Biso mean: 66.78 Å2 / Biso min: 38.96 Å2
Baniso -1Baniso -2Baniso -3
1--1.0613 Å20 Å20 Å2
2---1.0613 Å20 Å2
3---2.1225 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.124→21.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4640 0 78 217 4935
Biso mean--79.73 68.44 -
Num. residues----604
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2797SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1540HARMONIC5
X-RAY DIFFRACTIONt_it4842HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion634SEMIHARMONIC5
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_contact7056SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d9376HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg16888HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion3.09
X-RAY DIFFRACTIONt_other_torsion16.13
LS refinement shellResolution: 2.124→2.17 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.2636 38 4.33 %
Rwork0.2953 839 -
obs--26.83 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.3435-1.75190.67973.3425-0.09951.4266-0.20590.0468-0.52450.27410.13120.7937-0.0334-0.13720.0747-0.2371-0.00870.205-0.21280.0139-0.02855.000330.4456-28.5713
21.185-0.82640.82431.5273-1.01152.4133-0.1440.0560.19780.0208-0.2413-0.2775-0.08140.26720.3853-0.3141-0.05380.0102-0.07870.1899-0.1148-21.203627.1012-0.8647
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A26 - 330
2X-RAY DIFFRACTION2{ B|* }B31 - 330

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