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- PDB-7pwd: Structure of an inhibited GRK2-G-beta and G-gamma complex -

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Basic information

Entry
Database: PDB / ID: 7pwd
TitleStructure of an inhibited GRK2-G-beta and G-gamma complex
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Beta-adrenergic receptor kinase 1G protein-coupled receptor kinase 2
KeywordsTRANSFERASE / Proteros / GRK2 / Inhibition / Heart failure / Kinase
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
GPCR kinase / Regulator of G protein signaling domain / RGS, subdomain 2 / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. ...GPCR kinase / Regulator of G protein signaling domain / RGS, subdomain 2 / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS domain superfamily / 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 / 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 / PH-like domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / 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 / 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
Similarity search - Domain/homology
Chem-8DS / 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: 2.6 Å
AuthorsFaucher, N. / Tauchert, M.J. / Konz Makino, D.L. / Vuillard, L.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Monatsh Chem / Year: 2022
Title: Synthesis of thieno[2,3-c]pyridine derived GRK2 inhibitors
Authors: Balo, T. / Sapi, A. / Kiss, A. / Raimbaud, E. / Paysant, J. / Cattin, M.E. / Berger, S. / Kotschy, A. / Faucher, N.
History
DepositionOct 6, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 20, 2021Provider: repository / Type: Initial release
Revision 1.1May 18, 2022Group: Database references / Refinement description / Category: citation / citation_author / refine
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _refine.pdbx_diffrn_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)127,4938
Polymers126,7413
Non-polymers7535
Water3,045169
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7770 Å2
ΔGint-67 kcal/mol
Surface area48840 Å2
Unit cell
Length a, b, c (Å)185.600, 74.549, 123.411
Angle α, β, γ (deg.)90.000, 115.310, 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 / G protein-coupled receptor kinase 2 / Beta-ARK-1 / G-protein coupled receptor kinase 2


Mass: 80649.672 Da / Num. of mol.: 1 / Fragment: NONE / Mutation: S670A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRK2, ADRBK1, BARK, BARK1 / Production host: Spodoptera frugiperda (fall armyworm)
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: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62871
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 8673.959 Da / Num. of mol.: 1 / Mutation: C68S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Non-polymers , 5 types, 174 molecules

#4: Chemical ChemComp-8DS / 4-chloranyl-N-[2-(4-chlorophenyl)ethyl]thieno[2,3-c]pyridine-2-carboxamide


Mass: 351.250 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12Cl2N2OS / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#7: 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
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 169 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.29 Å3/Da / Density % sol: 62.59 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: ethylene glycol, PEG 3350, MES, NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.6→111.56 Å / Num. obs: 46426 / % possible obs: 98.2 % / Redundancy: 3.6 % / Biso Wilson estimate: 72.759 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.044 / Rrim(I) all: 0.053 / Χ2: 1.127 / Net I/σ(I): 16.24
Reflection shellResolution: 2.6→2.85 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.434 / Mean I/σ(I) obs: 3.5 / Num. unique obs: 11050 / CC1/2: 0.926 / Rrim(I) all: 0.508 / % possible all: 97.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASERphasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.6→111.56 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.944 / SU B: 23.83 / SU ML: 0.238 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.404 / ESU R Free: 0.256 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2295 869 1.9 %RANDOM
Rwork0.1917 ---
obs0.1924 45557 98.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 193.1 Å2 / Biso mean: 73.697 Å2 / Biso min: 36.52 Å2
Baniso -1Baniso -2Baniso -3
1-2.81 Å20 Å2-3.23 Å2
2--5.13 Å20 Å2
3----3.38 Å2
Refinement stepCycle: final / Resolution: 2.6→111.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8189 0 46 169 8404
Biso mean--83.56 60.9 -
Num. residues----1023
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0198193
X-RAY DIFFRACTIONr_bond_other_d0.0020.027716
X-RAY DIFFRACTIONr_angle_refined_deg1.1911.95611058
X-RAY DIFFRACTIONr_angle_other_deg0.919317703
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.12151020
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.78723.836365
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.0815.0041417
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0841551
X-RAY DIFFRACTIONr_chiral_restr0.0670.21209
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.029263
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021902
LS refinement shellResolution: 2.602→2.67 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.45 70 -
Rwork0.341 3279 -
all-3349 -
obs--96.68 %
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)
12.37060.3264-0.17372.5102-0.89125.83940.0927-0.02010.18650.0456-0.0813-0.1443-0.0144-0.053-0.01130.08170.0225-0.0040.1126-0.05640.123549.6527.89364.257
23.47941.5892-1.97986.0402-1.3525.87010.29210.04250.08560.5921-0.1925-0.1525-0.3459-0.0884-0.09960.10360.0478-0.05460.115-0.07940.107347.99727.94666.068
34.90760.04911.57521.92641.327111.17880.01530.45030.1054-0.59250.1579-0.3566-0.66310.45-0.17310.30050.00650.01090.31230.03390.298157.98131.41139.738
41.66940.1034-0.55023.21241.77772.33580.0287-0.2748-0.36860.5653-0.10630.21230.6707-0.42220.07750.277-0.1107-0.06510.431-0.0490.318137.3342.05162.266
53.1589-0.67170.8533.1059-1.14044.11690.0440.0526-0.3207-0.0609-0.1164-0.20090.59130.23270.07230.13530.0203-0.07210.18-0.07040.273446.703-7.8339.766
62.02662.22331.18566.8846-0.56571.5426-0.146-0.93780.64810.7457-0.32580.5563-0.6014-0.81940.47180.5360.21520.01480.6494-0.18030.571635.40337.99671.646
74.05990.71081.93796.30971.14335.83480.281-0.2178-0.30220.5632-0.25570.44810.9546-0.7283-0.02530.3018-0.08810.04710.2325-0.07320.126846.80522.83989.466
810.7609-0.21710.14640.65941.243513.2270.1802-0.3171-0.7065-0.0791-0.06430.13110.44591.0365-0.1160.27910.0341-0.03390.3418-0.01840.31865.4326.652102.91
93.86970.42371.93811.7484-0.34073.9899-0.1349-0.01920.4789-0.16880.0018-0.4213-0.13140.63680.1330.1063-0.1022-0.03010.2182-0.00150.268775.62345.693123.099
1000000000000000-00.2318000.231800.2318000
113.0671-0.19581.06231.21870.65593.0703-0.03120.15190.2008-0.11040.0138-0.1144-0.14820.36880.01740.0236-0.03480.01540.09360.00310.1363.44243.603110.633
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A33 - 77
2X-RAY DIFFRACTION2A160 - 185
3X-RAY DIFFRACTION3A78 - 159
4X-RAY DIFFRACTION4A186 - 272
5X-RAY DIFFRACTION4A498 - 525
6X-RAY DIFFRACTION5A273 - 475
7X-RAY DIFFRACTION6A526 - 552
8X-RAY DIFFRACTION7A553 - 655
9X-RAY DIFFRACTION8A656 - 668
10X-RAY DIFFRACTION9B2 - 39
11X-RAY DIFFRACTION9G8 - 38
12X-RAY DIFFRACTION9G41 - 70
13X-RAY DIFFRACTION10G39 - 40
14X-RAY DIFFRACTION11B40 - 340

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