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- PDB-4mk0: Crystal structure of G protein-coupled receptor kinase 2 in compl... -

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Basic information

Entry
Database: PDB / ID: 4mk0
TitleCrystal structure of G protein-coupled receptor kinase 2 in complex with a a rationally designed paroxetine derivative
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Beta-adrenergic receptor kinase 1G protein-coupled receptor kinase 2
KeywordsSIGNALING PROTEIN/inhibitor / INHIBITOR COMPLEX / PROTEIN KINASE / HYDROLASE / ATP BINDING / PHOSPHORYLATION / PERIPHERAL MEMBRANE PROTEIN / SIGNALING PROTEIN-inhibitor complex
Function / homology
Function and homology information


beta-adrenergic-receptor kinase / negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / tachykinin receptor signaling pathway / positive regulation of catecholamine secretion / Olfactory Signaling Pathway ...beta-adrenergic-receptor kinase / negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / tachykinin receptor signaling pathway / positive regulation of catecholamine secretion / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Activation of SMO / negative regulation of striated muscle contraction / desensitization of G protein-coupled receptor signaling pathway / regulation of the force of heart contraction / Activation of the phototransduction cascade / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / Calmodulin induced events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / cardiac muscle contraction / viral genome replication / G protein-coupled receptor binding / G protein-coupled acetylcholine receptor signaling pathway / receptor internalization / cilium / photoreceptor disc membrane / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / Cargo recognition for clathrin-mediated endocytosis / presynapse / heart development / G alpha (s) signalling events / postsynapse / G alpha (q) signalling events / peptidyl-serine phosphorylation / protein kinase activity / symbiont entry into host cell / G protein-coupled receptor signaling pathway / GTPase activity / ATP binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Helix Hairpins - #1270 / GPCR kinase / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Regulator of G-protein Signalling 4, domain 2 / Regulator of G-protein Signalling 4; domain 2 / Regulator of G protein signaling domain / RGS, subdomain 2 / RGS domain / RGS domain profile. ...Helix Hairpins - #1270 / GPCR kinase / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Regulator of G-protein Signalling 4, domain 2 / Regulator of G-protein Signalling 4; domain 2 / Regulator of G protein signaling domain / RGS, subdomain 2 / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS domain superfamily / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / YVTN repeat-like/Quinoprotein amine dehydrogenase / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 7 Propeller / Methylamine Dehydrogenase; Chain H / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / Few Secondary Structures / Irregular / Helix Hairpins / PH-like domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Roll / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-29X / Beta-adrenergic receptor kinase 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.4 Å
AuthorsHoman, K.T. / Tesmer, J.J.G.
CitationJournal: Mol.Pharmacol. / Year: 2014
Title: Structural and functional analysis of g protein-coupled receptor kinase inhibition by paroxetine and a rationally designed analog.
Authors: Homan, K.T. / Wu, E. / Wilson, M.W. / Singh, P. / Larsen, S.D. / Tesmer, J.J.
History
DepositionSep 4, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2017Group: Refinement description / Category: software
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-adrenergic receptor kinase 1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,7815
Polymers118,3513
Non-polymers4302
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6980 Å2
ΔGint-46 kcal/mol
Surface area47470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.222, 240.973, 212.083
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Beta-adrenergic receptor kinase 1 / G protein-coupled receptor kinase 2 / Beta-ARK-1 / G-protein coupled receptor kinase 2


Mass: 74545.641 Da / Num. of mol.: 1 / Fragment: unp residues 30-668
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADRBK1, BARK, BARK1, GRK2 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P25098, beta-adrenergic-receptor kinase

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62871
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6519.523 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63212

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Non-polymers , 3 types, 133 molecules

#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-29X / 5-{[(3S,4R)-4-(4-fluorophenyl)piperidin-3-yl]methoxy}-1H-isoindol-1-one


Mass: 338.375 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19FN2O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 131 / 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: 3.31 Å3/Da / Density % sol: 62.8 %
Crystal growTemperature: 277 K / pH: 7
Details: 6% PEG 3350, 1M NaCl, 2 mM MgCl2, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.1272
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Apr 12, 2012
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1272 Å / Relative weight: 1
ReflectionResolution: 2.4→19.99 Å / Num. obs: 29079 / % possible obs: 94.4 % / Observed criterion σ(I): 0 / Redundancy: 5 % / Biso Wilson estimate: 55.3 Å2 / Rsym value: 0.106 / Net I/σ(I): 15.4
Reflection shellResolution: 2.4→2.44 Å / Redundancy: 2.8 % / Mean I/σ(I) obs: 2.3 / Rsym value: 0.39 / % possible all: 1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMAC5.7.0032refinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→19.99 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.935 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 27.869 / SU ML: 0.249 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.396 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.238 1567 5.1 %RANDOM
Rwork0.175 ---
obs0.179 29079 49.7 %-
all-30646 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 102.99 Å2
Baniso -1Baniso -2Baniso -3
1--0.97 Å2-0 Å2-0 Å2
2--1.81 Å2-0 Å2
3----0.84 Å2
Refine analyze
FreeObs
Luzzati coordinate error39.6 Å24.9 Å
Refinement stepCycle: LAST / Resolution: 2.4→19.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8220 0 31 131 8382
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0198447
X-RAY DIFFRACTIONr_bond_other_d0.0010.028034
X-RAY DIFFRACTIONr_angle_refined_deg1.0661.9611391
X-RAY DIFFRACTIONr_angle_other_deg0.668318497
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.80351031
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.43523.725408
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.391151521
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2241567
X-RAY DIFFRACTIONr_chiral_restr0.0550.21226
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.029550
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021996
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.815.2434127
X-RAY DIFFRACTIONr_mcbond_other1.8085.2424126
X-RAY DIFFRACTIONr_mcangle_it3.0967.865157
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.47 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.406 2 -
Rwork0.27 66 -
obs--1.53 %
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)
17.5511-0.462-2.10036.14860.47543.2206-0.0514-0.97370.14110.8045-0.00491.24520.1158-0.39440.05640.30320.09340.30330.3710.00260.4424-44.272.73431.46
29.3378-1.7084-1.37976.31882.92577.2802-0.1683-0.03020.9157-0.65240.4639-1.1675-0.2691.0128-0.29550.22320.03940.13130.2179-0.03610.2951-17.15718.20516.18
35.5773-2.8686-0.75248.51652.36297.8726-0.0883-1.04481.23960.14931.0331-1.9328-0.52811.6252-0.94480.1309-0.0306-0.00990.5454-0.49890.8253-21.10935.98933.739
42.6481-1.5212-1.223811.322-3.07086.76960.32060.42340.0822-1.1377-0.2991-0.5354-0.21280.1813-0.02160.33550.03450.21530.1206-0.00750.1677-21.42-22.36915.865
52.1745-1.72370.16265.9449-0.76672.9410.10920.1084-0.3925-0.485-0.03110.57060.2292-0.0726-0.07810.13050.01170.04580.05-0.01910.1933-24.413-56.28926.514
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A30 - 184
2X-RAY DIFFRACTION1A513 - 547
3X-RAY DIFFRACTION1A801 - 817
4X-RAY DIFFRACTION2A185 - 274
5X-RAY DIFFRACTION2A475 - 512
6X-RAY DIFFRACTION2A818 - 834
7X-RAY DIFFRACTION2A702
8X-RAY DIFFRACTION3A275 - 474
9X-RAY DIFFRACTION3A835 - 846
10X-RAY DIFFRACTION4A548 - 669
11X-RAY DIFFRACTION4A847 - 859
12X-RAY DIFFRACTION5B2 - 340
13X-RAY DIFFRACTION5G6 - 64
14X-RAY DIFFRACTION5B401 - 468

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