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- PDB-6c2y: Human GRK2 in complex with Gbetagamma subunits and CCG257142 -

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Basic information

Entry
Database: PDB / ID: 6c2y
TitleHuman GRK2 in complex with Gbetagamma subunits and CCG257142
Components
  • Beta-adrenergic receptor kinase 1G protein-coupled receptor kinase 2
  • 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/Signaling Protein / TRANSFERASE-Signaling Protein 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 / positive regulation of catecholamine secretion / tachykinin receptor signaling pathway / 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 / positive regulation of catecholamine secretion / tachykinin receptor signaling pathway / 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 / Adrenaline,noradrenaline inhibits insulin secretion / 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 / 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 / Extra-nuclear estrogen signaling / G alpha (z) signalling events / 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 / cilium / receptor internalization / photoreceptor disc membrane / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / sensory perception of taste / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / Cargo recognition for clathrin-mediated endocytosis / presynapse / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / heart development / G alpha (s) signalling events / postsynapse / G alpha (q) signalling events / peptidyl-serine phosphorylation / cell population proliferation / protein kinase activity / symbiont entry into host cell / G protein-coupled receptor signaling pathway / GTPase activity / protein-containing complex binding / 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 / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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-EJS / 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 / Resolution: 2.74 Å
AuthorsBouley, R. / Tesmer, J.J.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01 HL071818 United States
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors.
Authors: Waldschmidt, H.V. / Bouley, R. / Kirchhoff, P.D. / Lee, P. / Tesmer, J.J.G. / Larsen, S.D.
History
DepositionJan 9, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 25, 2018Provider: repository / Type: Initial release
Revision 1.1May 2, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)126,3044
Polymers125,7683
Non-polymers5371
Water75742
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6720 Å2
ΔGint-46 kcal/mol
Surface area46240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.557, 240.453, 212.796
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 / G protein-coupled receptor kinase 2 / Beta-ARK-1 / G-protein coupled receptor kinase 2


Mass: 79676.641 Da / Num. of mol.: 1 / Mutation: S670A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRK2, ADRBK1, BARK, BARK1
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
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.) Bos taurus (cattle) / Gene: GNB1
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
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 aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: P63212
#4: Chemical ChemComp-EJS / (4R,5R,6S)-4-[4-fluoro-3-({[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}carbamoyl)phenyl]-N-(2H-indazol-5-yl)-6-methyl-2-oxohexahydropyrimidine-5-carboxamide


Mass: 536.515 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25FN8O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 42 / 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: 3.08 Å3/Da / Density % sol: 60.06 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 50 mM MES pH 6.0, 800 mM NaCl, 8% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.74→48.32 Å / Num. obs: 40501 / % possible obs: 96 % / Redundancy: 14.1 % / CC1/2: 0.991 / Rmerge(I) obs: 0.3044 / Rrim(I) all: 0.3161 / Net I/σ(I): 5.62
Reflection shellResolution: 2.74→2.838 Å / Redundancy: 14.6 % / Rmerge(I) obs: 2.061 / Mean I/σ(I) obs: 1.17 / Num. unique obs: 4026 / CC1/2: 0.705 / Rrim(I) all: 2.137 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4PNK

4pnk


Resolution: 2.74→48.32 Å / SU ML: 0.4 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 32.98
RfactorNum. reflection% reflection
Rfree0.2916 1965 4.95 %
Rwork0.2443 --
obs0.2466 39679 95.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.74→48.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8078 0 39 42 8159
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0018286
X-RAY DIFFRACTIONf_angle_d0.43911168
X-RAY DIFFRACTIONf_dihedral_angle_d18.1933112
X-RAY DIFFRACTIONf_chiral_restr0.0381200
X-RAY DIFFRACTIONf_plane_restr0.0021446
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.74-2.80850.38241420.38742553X-RAY DIFFRACTION93
2.8085-2.88450.39481260.38642636X-RAY DIFFRACTION94
2.8845-2.96930.40441290.36222622X-RAY DIFFRACTION95
2.9693-3.06520.38981350.35492679X-RAY DIFFRACTION97
3.0652-3.17470.42191330.33742718X-RAY DIFFRACTION97
3.1747-3.30180.31021510.32012679X-RAY DIFFRACTION97
3.3018-3.45210.34891410.29282720X-RAY DIFFRACTION97
3.4521-3.6340.32591570.26812731X-RAY DIFFRACTION98
3.634-3.86160.27641390.24492763X-RAY DIFFRACTION98
3.8616-4.15970.29931570.21952746X-RAY DIFFRACTION98
4.1597-4.57810.24781310.19082745X-RAY DIFFRACTION96
4.5781-5.240.24751200.17642345X-RAY DIFFRACTION83
5.24-6.59990.22761370.20962864X-RAY DIFFRACTION99
6.5999-53.2090.24551670.19292913X-RAY DIFFRACTION97
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)
13.15-1.2324-1.41292.38071.31373.4475-0.1734-0.5142-0.37060.2718-0.13940.87680.5075-0.44380.30750.5963-0.00730.28180.74210.0530.9766-44.57443.389631.7433
22.2995-0.67540.38352.5610.69141.4616-0.1572-0.09710.2037-0.42210.0708-0.61910.08750.6024-0.03160.57230.11090.1740.70090.01310.6073-17.4617.158716.0146
34.7671-2.2316-0.44515.1290.02753.59250.0554-0.81060.78860.0710.2487-1.0479-0.56950.9835-0.17090.544-0.10890.11690.8713-0.18930.728-21.392936.416232.6819
41.07780.729-0.34631.4570.33530.80520.14380.20340.0756-0.5791-0.0386-0.0934-0.0330.04970.05030.59480.06370.1660.36840.01560.4913-21.9099-21.65216.0189
51.4841-1.04980.08063.8302-0.64111.7430.04380.0648-0.221-0.36620.04320.34220.047-0.0318-0.07120.5372-0.01070.16340.4624-0.00930.5209-24.583-55.817326.7465
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 30:184 OR RESID 513:548 OR RESID 812:821 ) )A30 - 184
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 30:184 OR RESID 513:548 OR RESID 812:821 ) )A513 - 548
3X-RAY DIFFRACTION1( CHAIN A AND ( RESID 30:184 OR RESID 513:548 OR RESID 812:821 ) )A812 - 821
4X-RAY DIFFRACTION2( CHAIN A AND ( RESID 185:274 OR RESID 493:512 OR RESID 701:701 ) )A185 - 274
5X-RAY DIFFRACTION2( CHAIN A AND ( RESID 185:274 OR RESID 493:512 OR RESID 701:701 ) )A493 - 512
6X-RAY DIFFRACTION2( CHAIN A AND ( RESID 185:274 OR RESID 493:512 OR RESID 701:701 ) )A701
7X-RAY DIFFRACTION3( CHAIN A AND RESID 275:474 )A275 - 474
8X-RAY DIFFRACTION4( CHAIN A AND RESID 551:668 )A551 - 668
9X-RAY DIFFRACTION5( CHAIN B AND ( RESID 2:340 OR RESID 401:417 ) ) OR ( CHAIN G AND ( RESID 7:63 OR RESID 101:101 ) )B2 - 340
10X-RAY DIFFRACTION5( CHAIN B AND ( RESID 2:340 OR RESID 401:417 ) ) OR ( CHAIN G AND ( RESID 7:63 OR RESID 101:101 ) )B401 - 417
11X-RAY DIFFRACTION5( CHAIN B AND ( RESID 2:340 OR RESID 401:417 ) ) OR ( CHAIN G AND ( RESID 7:63 OR RESID 101:101 ) )G7 - 63
12X-RAY DIFFRACTION5( CHAIN B AND ( RESID 2:340 OR RESID 401:417 ) ) OR ( CHAIN G AND ( RESID 7:63 OR RESID 101:101 ) )G101

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