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- PDB-4pnk: G protein-coupled receptor kinase 2 in complex with GSK180736A -

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Basic information

Entry
Database: PDB / ID: 4pnk
TitleG protein-coupled receptor kinase 2 in complex with GSK180736A
Components
  • Beta-adrenergic receptor kinase 1
  • Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
KeywordsTransferase/Transferase inhibitor / PROTEIN KINASE / HYDROLASE / ATP BINDING / PHOSPHORYLATION / PERIPHERAL MEMBRANE PROTEIN / Transferase-Transferase inhibitor complex
Function / homology
Function and homology information


negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / 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 / negative regulation of striated muscle contraction ...negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / 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 / negative regulation of striated muscle contraction / Activation of SMO / desensitization of G protein-coupled receptor signaling pathway / cytoplasmic side of mitochondrial outer membrane / regulation of the force of heart contraction / Calmodulin induced events / 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 / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / cardiac muscle contraction / viral genome replication / G protein-coupled receptor binding / receptor internalization / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Cargo recognition for clathrin-mediated endocytosis / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / presynapse / Thrombin signalling through proteinase activated receptors (PARs) / peptidyl-serine phosphorylation / heart development / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / postsynapse / protein kinase activity
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 domain / RGS domain profile. / Regulator of G protein signalling domain ...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 domain / RGS domain profile. / Regulator of G protein signalling domain / RGS, subdomain 2 / RGS domain superfamily / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Few Secondary Structures / Irregular / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / Helix Hairpins / PH-like domain superfamily / G-protein beta WD-40 repeat / Roll / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Phosphorylase Kinase; domain 1 / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / WD40 repeats / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40 repeat / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / 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-KZQ / 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 (domestic cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.56 Å
AuthorsHoman, K.T. / Larimore, K.M. / Elkins, J. / Knapp, S. / Tesmer, J.J.G.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL071818 and HL086865 United States
American Heart AssociationN014938 United States
CitationJournal: Acs Chem.Biol. / Year: 2015
Title: Identification and structure-function analysis of subfamily selective g protein-coupled receptor kinase inhibitors.
Authors: Homan, K.T. / Larimore, K.M. / Elkins, J.M. / Szklarz, M. / Knapp, S. / Tesmer, J.J.
History
DepositionMay 23, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 8, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 24, 2014Group: Database references
Revision 1.2Jan 28, 2015Group: Database references
Revision 1.3Sep 6, 2017Group: Author supporting evidence / Derived calculations ...Author supporting evidence / Derived calculations / Other / Source and taxonomy
Category: entity_src_gen / pdbx_audit_support ...entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_oper_list
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Dec 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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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)125,3204
Polymers124,9553
Non-polymers3651
Water1,24369
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6870 Å2
ΔGint-46 kcal/mol
Surface area47450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.435, 241.398, 212.526
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 79692.641 Da / Num. of mol.: 1
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
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7845.078 Da / Num. of mol.: 1 / Mutation: C68S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Trioceros cristatus (reptile) / References: UniProt: P63212
#4: Chemical ChemComp-KZQ / (4S)-4-(4-fluorophenyl)-N-(2H-indazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide


Mass: 365.361 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H16FN5O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.15 Å3/Da / Density % sol: 60.99 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: MES, PEG 3350, NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 14, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 2.56→25 Å / Num. obs: 51212 / % possible obs: 100 % / Redundancy: 26.2 % / Rsym value: 0.201 / Net I/σ(I): 18.7
Reflection shellResolution: 2.56→2.63 Å / Redundancy: 25.6 % / Mean I/σ(I) obs: 1.8 / % possible all: 100

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Processing

SoftwareName: REFMAC / Version: 5.7.0032 / Classification: refinement
RefinementResolution: 2.56→24.55 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.94 / SU B: 30.764 / SU ML: 0.279 / Cross valid method: THROUGHOUT / ESU R: 0.379 / ESU R Free: 0.284 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25928 2565 5.1 %RANDOM
Rwork0.19032 ---
obs0.19382 47772 97.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 102.735 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å2-0 Å2
2---0.69 Å20 Å2
3---0.67 Å2
Refinement stepCycle: 1 / Resolution: 2.56→24.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8214 0 27 69 8310
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0198428
X-RAY DIFFRACTIONr_bond_other_d0.0010.028011
X-RAY DIFFRACTIONr_angle_refined_deg1.9141.9611363
X-RAY DIFFRACTIONr_angle_other_deg0.9318444
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.85151025
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.17423.735407
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.171151525
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.6661566
X-RAY DIFFRACTIONr_chiral_restr0.0970.21221
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.029518
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021998
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_it3.6734.7634109
X-RAY DIFFRACTIONr_mcbond_other3.674.7634108
X-RAY DIFFRACTIONr_mcangle_it5.3647.1415131
X-RAY DIFFRACTIONr_mcangle_other5.3637.1425132
X-RAY DIFFRACTIONr_scbond_it3.945.074319
X-RAY DIFFRACTIONr_scbond_other3.945.074320
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.8267.4756233
X-RAY DIFFRACTIONr_long_range_B_refined7.55637.79609
X-RAY DIFFRACTIONr_long_range_B_other7.55637.7019610
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.56→2.625 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.399 144 -
Rwork0.317 2677 -
obs--76.33 %
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)
14.3945-0.347-1.8964.62150.31193.4926-0.1583-0.5403-0.15770.6380.01451.1892-0.0127-0.4480.14380.4080.09690.26040.62140.03990.4016-44.462.47231.657
27.8878-1.6304-1.47125.35982.15995.6983-0.195-0.24650.8164-0.6640.4208-1.0742-0.22741.0217-0.22580.33820.0380.12030.5446-0.05340.2649-17.11417.68716.293
35.0212-3.5972-0.95047.94262.13385.7769-0.0758-0.8681.36790.21170.9876-1.966-0.51321.3724-0.91180.2254-0.0337-0.05510.8083-0.49640.7612-21.2736.13633.746
43.6237-0.8375-0.684310.7309-3.11754.87570.28620.40160.1066-0.9714-0.1259-0.6927-0.15310.1569-0.16040.43580.08320.19450.38120.00660.1075-21.557-22.35315.764
51.5309-1.42630.14595.6985-0.74281.67830.1150.1247-0.3769-0.52010.03930.59610.1941-0.0266-0.15420.2590.03260.01480.3969-0.0330.1561-24.794-56.51226.261
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A30 - 184
2X-RAY DIFFRACTION1A513 - 547
3X-RAY DIFFRACTION1A802 - 807
4X-RAY DIFFRACTION2A185 - 274
5X-RAY DIFFRACTION2A476 - 512
6X-RAY DIFFRACTION2A808 - 817
7X-RAY DIFFRACTION2A701
8X-RAY DIFFRACTION3A275 - 474
9X-RAY DIFFRACTION3A818 - 827
10X-RAY DIFFRACTION4A548 - 668
11X-RAY DIFFRACTION4B401 - 403
12X-RAY DIFFRACTION5B2 - 340
13X-RAY DIFFRACTION5G7 - 68
14X-RAY DIFFRACTION5B404 - 432
15X-RAY DIFFRACTION5G101 - 102

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