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- PDB-5l4q: Crystal Structure of Adaptor Protein 2 Associated Kinase 1 (AAK1)... -

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Basic information

Entry
Database: PDB / ID: 5l4q
TitleCrystal Structure of Adaptor Protein 2 Associated Kinase 1 (AAK1) in Complex with LKB1 (AAK1 Dual Inhibitor)
ComponentsAP2-associated protein kinase 1
KeywordsTRANSFERASE / Kinase Kinase domain
Function / homology
Function and homology information


presynaptic endocytosis / regulation of clathrin-dependent endocytosis / AP-2 adaptor complex binding / membrane organization / Notch binding / clathrin-coated vesicle / positive regulation of Notch signaling pathway / cell leading edge / clathrin-coated pit / terminal bouton ...presynaptic endocytosis / regulation of clathrin-dependent endocytosis / AP-2 adaptor complex binding / membrane organization / Notch binding / clathrin-coated vesicle / positive regulation of Notch signaling pathway / cell leading edge / clathrin-coated pit / terminal bouton / regulation of protein localization / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / 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
Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-LKB / AP2-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.97 Å
AuthorsSorrell, F.J. / Williams, E. / Fox, N. / Abdul Azeez, K.R. / Gileadi, O. / von Delft, F. / Edwards, A.M. / Bountra, C. / Elkins, J.M. / Knapp, S.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity.
Authors: Verdonck, S. / Pu, S.Y. / Sorrell, F.J. / Elkins, J.M. / Froeyen, M. / Gao, L.J. / Prugar, L.I. / Dorosky, D.E. / Brannan, J.M. / Barouch-Bentov, R. / Knapp, S. / Dye, J.M. / Herdewijn, P. / ...Authors: Verdonck, S. / Pu, S.Y. / Sorrell, F.J. / Elkins, J.M. / Froeyen, M. / Gao, L.J. / Prugar, L.I. / Dorosky, D.E. / Brannan, J.M. / Barouch-Bentov, R. / Knapp, S. / Dye, J.M. / Herdewijn, P. / Einav, S. / De Jonghe, S.
History
DepositionMay 26, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 8, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)78,7066
Polymers77,9032
Non-polymers8034
Water3,963220
1
A: AP2-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3533
Polymers38,9521
Non-polymers4012
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)39,3533
Polymers38,9521
Non-polymers4012
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)61.800, 55.050, 86.570
Angle α, β, γ (deg.)90.000, 104.440, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21chain B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLY / Beg label comp-ID: GLY

Dom-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1GLUGLUchain AAA33 - 3357 - 309
2LEULEUchain BBB33 - 3337 - 307

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Components

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


Mass: 38951.645 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AAK1, KIAA1048 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q2M2I8, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-LKB / ~{N}-[5-(4-cyanophenyl)-1~{H}-pyrrolo[2,3-b]pyridin-3-yl]pyridine-3-carboxamide


Mass: 339.350 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H13N5O
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 220 / Source method: isolated from a natural source / Formula: H2O

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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: 1.83 Å3/Da / Density % sol: 32.81 % / Description: thick rectangular plate
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 0.1M bis-tris pH 5.5, 26% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 15, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.97→46.02 Å / Num. obs: 39653 / % possible obs: 99 % / Redundancy: 3.3 % / CC1/2: 0.993 / Rmerge(I) obs: 0.108 / Net I/σ(I): 10.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
1.97-2.023.40.917199.2
8.81-46.023.20.021198.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.97 Å46.02 Å
Translation5.46 Å46.02 Å

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Processing

Software
NameVersionClassification
Aimless0.5.23data scaling
PHASER2.5.5phasing
PHENIXrefinement
PDB_EXTRACT3.2data extraction
Cootmodel building
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4wsq

4wsq


Resolution: 1.97→46.016 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.87
RfactorNum. reflection% reflectionSelection details
Rfree0.2265 1936 4.89 %Random selection
Rwork0.2071 ---
obs0.208 39628 98.84 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 127.41 Å2 / Biso mean: 44.2379 Å2 / Biso min: 0 Å2
Refinement stepCycle: final / Resolution: 1.97→46.016 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4551 0 98 220 4869
Biso mean--35.21 40.69 -
Num. residues----580
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034727
X-RAY DIFFRACTIONf_angle_d0.7426406
X-RAY DIFFRACTIONf_chiral_restr0.031718
X-RAY DIFFRACTIONf_plane_restr0.003877
X-RAY DIFFRACTIONf_dihedral_angle_d11.6531766
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A3380X-RAY DIFFRACTION7.153TORSIONAL
12B3380X-RAY DIFFRACTION7.153TORSIONAL
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.97-2.01930.37591410.32812666X-RAY DIFFRACTION99
2.0193-2.07390.31421460.30222680X-RAY DIFFRACTION99
2.0739-2.13490.2781160.2882693X-RAY DIFFRACTION99
2.1349-2.20380.30791470.26662689X-RAY DIFFRACTION99
2.2038-2.28260.291260.26332665X-RAY DIFFRACTION98
2.2826-2.37390.31461380.24552695X-RAY DIFFRACTION99
2.3739-2.4820.23481500.23962651X-RAY DIFFRACTION99
2.482-2.61280.22471340.2222715X-RAY DIFFRACTION100
2.6128-2.77650.21831300.2072714X-RAY DIFFRACTION99
2.7765-2.99080.2551470.21692700X-RAY DIFFRACTION99
2.9908-3.29180.19251310.19612708X-RAY DIFFRACTION99
3.2918-3.76790.19881480.18142662X-RAY DIFFRACTION98
3.7679-4.74640.1811360.15762670X-RAY DIFFRACTION97
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)
12.7401-0.83790.4622.5099-0.70892.27550.0074-0.0887-0.0294-0.09420.05570.3261-0.0625-0.2118-0.05220.3214-0.0157-0.03250.25460.01170.3162-28.9858-6.9087-29.4185
22.1414-0.1653-0.31251.8346-0.23332.11960.0915-0.08390.07950.0053-0.0843-0.0499-0.13590.03780.00720.3125-0.0038-0.03350.24780.01490.2979-11.6355-5.4667-41.1599
31.0838-0.3306-1.41481.60950.54111.8562-0.27850.1798-0.1792-0.25890.1893-0.57380.18950.21060.04110.8829-0.1325-0.07410.63630.00561.0061.28045.086-45.0378
42.5328-0.0560.64841.5689-0.22242.0016-0.0169-0.047-0.31870.0714-0.1585-0.5652-0.06630.3610.09480.32980.0036-0.04420.33780.06440.47071.9413-12.3134-43.2459
53.03430.2765-0.19791.7789-0.21521.9496-0.06910.08330.25970.30010.07910.0819-0.1268-0.06180.02650.45860.0094-0.11960.28150.03360.3682-13.1725-20.1723-8.0628
61.92910.3599-0.60482.23140.79271.8702-0.0787-0.0107-0.10610.03230.0974-0.10280.3689-0.0624-0.02270.4139-0.0196-0.08640.26010.02280.32457.3263-21.9793-4.3644
75.58350.25061.43851.8148-0.31311.01420.1667-0.2907-0.2868-0.1183-0.1453-0.15770.82750.4570.14941.10280.10870.13710.48240.04970.618820.0314-33.3474-7.5275
82.2066-0.186-0.43311.9146-0.19742.4270.0095-0.07930.0191-0.06390.07-0.3918-0.03120.3679-0.0970.3594-0.0129-0.03610.3311-0.0090.41520.5177-15.6463-8.419
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 34:132)A34 - 132
2X-RAY DIFFRACTION2(chain A and resid 133:258)A133 - 258
3X-RAY DIFFRACTION3(chain A and resid 259:280)A259 - 280
4X-RAY DIFFRACTION4(chain A and resid 281:333)A281 - 333
5X-RAY DIFFRACTION5(chain B and resid 33:132)B33 - 132
6X-RAY DIFFRACTION6(chain B and resid 133:257)B133 - 257
7X-RAY DIFFRACTION7(chain B and resid 258:279)B258 - 279
8X-RAY DIFFRACTION8(chain B and resid 280:333)B280 - 333

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