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- PDB-5ukm: bovine GRK2 in complex with human Gbetagamma subunits and CCG2582... -

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Basic information

Entry
Database: PDB / ID: 5ukm
Titlebovine GRK2 in complex with human Gbetagamma subunits and CCG258208 (14as)
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Beta-adrenergic receptor kinase 1
KeywordsTransferase/Signaling Protein / kinase / inhibitor complex / Transferase-Signaling Protein complex
Function / homology
Function and homology information


Calmodulin induced events / negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / Activation of SMO / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / tachykinin receptor signaling pathway ...Calmodulin induced events / negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / Activation of SMO / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / tachykinin receptor signaling pathway / negative regulation of striated muscle contraction / Cargo recognition for clathrin-mediated endocytosis / positive regulation of protein localization to cilium / desensitization of G protein-coupled receptor signaling pathway / cytoplasmic side of mitochondrial outer membrane / regulation of the force of heart contraction / positive regulation of smoothened signaling pathway / G protein-coupled receptor internalization / G alpha (s) signalling events / G alpha (q) signalling events / regulation of signal transduction / cardiac muscle contraction / adenylate cyclase-activating adrenergic receptor signaling pathway / viral genome replication / cell projection / intracellular protein transport / G protein-coupled receptor binding / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / 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 / sensory perception of taste / presynapse / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / heart development / retina development in camera-type eye / GTPase binding / Ca2+ pathway / fibroblast proliferation / 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 / protein phosphorylation / protein kinase activity / postsynapse / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / symbiont entry into host cell / protein-containing complex binding / signal transduction / extracellular exosome / ATP binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Helix Hairpins - #1270 / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / GPCR kinase / 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 / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / GPCR kinase / 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. / YVTN repeat-like/Quinoprotein amine dehydrogenase / Pleckstrin homology domain / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / Helix Hairpins / PH-like domain superfamily / WD domain, G-beta repeat / Roll / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Phosphorylase Kinase; domain 1 / Trp-Asp (WD) repeats signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / Protein kinase domain / WD40-repeat-containing domain superfamily / 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
O-METHYLCYSTEINE / Chem-T0E / 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
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.03 Å
AuthorsCruz-Rodriguez, O. / Tesmer, J.J.G.
Funding support United States, 11items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL071818 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL086865 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL122416 United States
American Heart AssociationN014938 United States
American Heart Association15PRE22730028 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R37 HL061690 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL075443 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL108806 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL091799 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5T32GM008597 United States
Michigan Economic Development Corporation and Michigan Technology Tri-Corridor085P1000817 United States
CitationJournal: J. Med. Chem. / Year: 2017
Title: Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.
Authors: Waldschmidt, H.V. / Homan, K.T. / Cato, M.C. / Cruz-Rodriguez, O. / Cannavo, A. / Wilson, M.W. / Song, J. / Cheung, J.Y. / Koch, W.J. / Tesmer, J.J. / Larsen, S.D.
History
DepositionJan 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 12, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2017Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn_type.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)127,5866
Polymers126,9743
Non-polymers6123
Water41423
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6850 Å2
ΔGint-49 kcal/mol
Surface area47640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)189.012, 74.150, 123.175
Angle α, β, γ (deg.)90.000, 115.460, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 80578.820 Da / Num. of mol.: 1 / Mutation: S670A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GRK2, ADRBK1 / Plasmid: pFastBacDual / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P21146, 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: 38534.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Plasmid: pFastBacDual / 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: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Plasmid: pFastBacDual / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Non-polymers , 4 types, 26 molecules

#4: Chemical ChemComp-T0E / 5-[(3S,4R)-3-{[(2H-1,3-benzodioxol-5-yl)oxy]methyl}piperidin-4-yl]-2-fluoro-N-[(1H-pyrazol-5-yl)methyl]benzamide


Mass: 452.478 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H25FN4O4
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-CMT / O-METHYLCYSTEINE


Type: L-peptide linking / Mass: 135.185 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H9NO2S
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 3.34 Å3/Da / Density % sol: 63.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: 100 mM MES, 0.2 M NaCl, 8-10% PEG3350 / PH range: 6.4-6.7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.97857 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 16, 2015
RadiationMonochromator: Diamond [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 3.03→30 Å / Num. obs: 29942 / % possible obs: 98.5 % / Observed criterion σ(I): -3 / Redundancy: 6.942 % / Biso Wilson estimate: 69.782 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.119 / Rrim(I) all: 0.129 / Χ2: 0.924 / Net I/σ(I): 12.84 / Num. measured all: 207868
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
3.03-3.217.0550.9321.9846570.8941.00796
3.21-3.436.9390.5313.5245420.9630.57499.5
3.43-3.76.3940.2966.0141750.9830.32297.8
3.7-4.067.1960.18410.6439070.9920.19899.7
4.06-4.537.2740.10616.4235560.9970.11599.8
4.53-5.227.2070.07621.7731390.9970.08299.3
5.22-6.386.9110.07721.2326650.9970.08499
6.38-8.946.5090.05328.3420750.9980.05898.2
8.94-306.7480.03841.1812260.9990.04197.8

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PDB_EXTRACT3.22data extraction
REFMACrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3V5W

3v5w


Resolution: 3.03→30 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.91 / SU B: 52.885 / SU ML: 0.404 / SU R Cruickshank DPI: 0.3341 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.419
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2516 1479 4.9 %RANDOM
Rwork0.1971 ---
obs0.1997 28446 98.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 227.13 Å2 / Biso mean: 104.392 Å2 / Biso min: 50.77 Å2
Baniso -1Baniso -2Baniso -3
1--0.66 Å20 Å21.03 Å2
2---1.53 Å2-0 Å2
3---0.83 Å2
Refinement stepCycle: final / Resolution: 3.03→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8175 0 42 23 8240
Biso mean--121.12 73.47 -
Num. residues----1020
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0198398
X-RAY DIFFRACTIONr_bond_other_d0.0020.027987
X-RAY DIFFRACTIONr_angle_refined_deg1.5631.96211318
X-RAY DIFFRACTIONr_angle_other_deg0.987318393
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.07351017
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.17523.753405
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.13151519
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0361565
X-RAY DIFFRACTIONr_chiral_restr0.0810.21219
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029456
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021980
LS refinement shellResolution: 3.027→3.105 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.486 116 -
Rwork0.323 1913 -
all-2029 -
obs--91.77 %
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)
10.72070.33510.29890.3317-0.45382.4287-0.0928-0.0370.289-0.0064-0.1150.04910.0738-0.05560.20770.85710.0275-0.33391.1333-0.02010.3703-16.2478-6.3815-1.8687
23.4536-0.3783-2.93965.909-2.02643.55470.13010.0702-0.48890.6185-0.429-0.2278-0.0899-0.21710.29891.0351-0.6696-0.65651.34280.35620.4636-28.5053-37.91464.9636
31.6445-0.7314-0.24521.5938-0.2390.98780.14590.2453-0.43510.1566-0.1634-0.3026-0.0477-0.16830.01750.6958-0.0428-0.49770.9804-0.15760.6493-19.8202-43.4392-18.202
40.67770.03080.8330.93140.96573.10440.1358-0.16160.14820.0685-0.073-0.08430.6358-0.3721-0.06290.8599-0.1684-0.23831.267-0.12460.1751-17.2708-13.547734.8729
51.47730.14830.64610.19790.48781.5267-0.08830.1892-0.02370.00680.22840.0127-0.02850.3297-0.14020.7018-0.0526-0.21511.3142-0.13740.30890.43127.678356.6508
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A31 - 184
2X-RAY DIFFRACTION1A513 - 547
3X-RAY DIFFRACTION2A185 - 270
4X-RAY DIFFRACTION2L1
5X-RAY DIFFRACTION2A496 - 512
6X-RAY DIFFRACTION3A271 - 484
7X-RAY DIFFRACTION4A548 - 669
8X-RAY DIFFRACTION5B2 - 340
9X-RAY DIFFRACTION5G8 - 68

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