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- PDB-8gmc: CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 COMPLEXED WITH 5-[(4... -

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Basic information

Entry
Database: PDB / ID: 8gmc
TitleCRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 COMPLEXED WITH 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
ComponentsAP2-associated protein kinase 1
KeywordsTRANSFERASE / AP2 ASSOCIATED KINASE 1 / AAK1 / kinase / ligand inhibitor
Function / homology
Function and homology information


regulation of clathrin-dependent endocytosis / AP-2 adaptor complex binding / membrane organization / Notch binding / clathrin-coated vesicle / positive regulation of Notch signaling pathway / presynaptic endocytosis / cell leading edge / clathrin-coated pit / terminal bouton ...regulation of clathrin-dependent endocytosis / AP-2 adaptor complex binding / membrane organization / Notch binding / clathrin-coated vesicle / positive regulation of Notch signaling pathway / presynaptic endocytosis / cell leading edge / clathrin-coated pit / terminal bouton / Cargo recognition for clathrin-mediated endocytosis / presynapse / Clathrin-mediated endocytosis / regulation of protein localization / protein phosphorylation / non-specific serine/threonine protein kinase / protein stabilization / 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-YFV / AP2-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsMuckelbauer, J.K.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Med.Chem.Res. / Year: 2023
Title: Discovery of pyrrolo[2,1- f ][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.
Authors: Dzierba, C.D. / Dasgupta, B. / Karageorge, G. / Kostich, W. / Hamman, B. / Allen, J. / Esposito, K.M. / Padmanabha, R. / Grace, J. / Lentz, K. / Morrison, J. / Morgan, D. / Easton, A. / ...Authors: Dzierba, C.D. / Dasgupta, B. / Karageorge, G. / Kostich, W. / Hamman, B. / Allen, J. / Esposito, K.M. / Padmanabha, R. / Grace, J. / Lentz, K. / Morrison, J. / Morgan, D. / Easton, A. / Bourin, C. / Browning, M.R. / Rajamani, R. / Good, A. / Parker, D.D. / Muckelbauer, J.K. / Khan, J. / Camac, D. / Ghosh, K. / Halan, V. / Lippy, J.S. / Santone, K.S. / Denton, R.R. / Westphal, R. / Bristow, L.J. / Conway, C.M. / Bronson, J.J. / Macor, J.E.
History
DepositionMar 24, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 12, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)73,4728
Polymers72,1912
Non-polymers1,2816
Water1,33374
1
A: AP2-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8325
Polymers36,0951
Non-polymers7374
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: AP2-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6403
Polymers36,0951
Non-polymers5452
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)74.778, 74.778, 310.850
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

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


Mass: 36095.391 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-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.: 2 / Source method: obtained synthetically / Formula: C23H28N8S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 74 / 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: 3.01 Å3/Da / Density % sol: 59.13 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 1.2M AmSO4, 0.1M tri-Na Citrate pH 6.0, 3% isopropanol, 296K

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-BM / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jul 24, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 31551 / % possible obs: 99.5 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 18.4
Reflection shellResolution: 2.5→2.59 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.633 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 5895 / % possible all: 100

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Processing

Software
NameClassification
BUSTERrefinement
HKL-2000data reduction
PHASERphasing
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7rj6

7rj6


Resolution: 2.5→32.53 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.896 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.237
RfactorNum. reflection% reflectionSelection details
Rfree0.256 1592 5.05 %RANDOM
Rwork0.227 ---
obs0.228 31551 99.5 %-
Displacement parametersBiso mean: 44.67 Å2
Baniso -1Baniso -2Baniso -3
1--4.2512 Å20 Å20 Å2
2---4.2512 Å20 Å2
3---8.5025 Å2
Refine analyzeLuzzati coordinate error obs: 0.381 Å
Refinement stepCycle: LAST / Resolution: 2.5→32.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4442 0 84 74 4600
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014618HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.146281HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1523SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes107HARMONIC2
X-RAY DIFFRACTIONt_gen_planes724HARMONIC5
X-RAY DIFFRACTIONt_it4618HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.14
X-RAY DIFFRACTIONt_other_torsion18.12
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion615SEMIHARMONIC5
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_contact5275SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.58 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.3142 140 4.91 %
Rwork0.2672 2714 -
all0.2696 2854 -
obs--100 %

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