[English] 日本語
Yorodumi
- PDB-7k7z: Structure of a hit for G Protein Coupled Receptor Kinase 2 (GRK2)... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 7k7z
TitleStructure of a hit for G Protein Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
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
KeywordsSIGNALING PROTEIN / TRANSFERASE/INHIBITOR / serine/threonine protein kinase / TRANSFERASE-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 / positive regulation of catecholamine secretion / tachykinin receptor signaling pathway / Activation of SMO ...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 / Activation of SMO / negative regulation of striated muscle contraction / desensitization of G protein-coupled receptor signaling pathway / regulation of the force of heart contraction / Calmodulin induced events / cardiac muscle contraction / viral genome replication / 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 activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / cilium / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / receptor internalization / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / Cargo recognition for clathrin-mediated endocytosis / presynapse / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / heart development / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / postsynapse / G alpha (q) signalling events / peptidyl-serine phosphorylation / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / protein kinase activity / symbiont entry into host cell / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / 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. / 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 / 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
3-benzyl-7-(1H-pyrazol-4-yl)quinazolin-4(3H)-one / 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 speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.60608692764 Å
AuthorsSpurlino, J.C. / Milligan, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor.
Authors: Xu, G. / Gaul, M.D. / Liu, Z. / DesJarlais, R.L. / Qi, J. / Wang, W. / Krosky, D. / Petrounia, I. / Milligan, C.M. / Hermans, A. / Lu, H.R. / Huang, D.Z. / Xu, J.Z. / Spurlino, J.C.
History
DepositionSep 24, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 28, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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)118,6534
Polymers118,3513
Non-polymers3021
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6560 Å2
ΔGint-50 kcal/mol
Surface area46290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)194.679, 70.689, 111.503
Angle α, β, γ (deg.)90.000, 110.460, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y

-
Components

#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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRK2, ADRBK1, BARK, BARK1 / Production host: unidentified baculovirus
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: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: unidentified baculovirus / References: UniProt: P62873
#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.) Homo sapiens (human) / Gene: GNG2 / Production host: unidentified baculovirus / References: UniProt: P59768
#4: Chemical ChemComp-W4G / 3-benzyl-7-(1H-pyrazol-4-yl)quinazolin-4(3H)-one


Mass: 302.330 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H14N4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 3.04 Å3/Da / Density % sol: 59.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 2% PEG 3350, 0.1M MES pH 6.5, 0.2M NaCl

-
Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Oct 13, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 43160 / % possible obs: 99.2 % / Redundancy: 3.4 % / Biso Wilson estimate: 52.338872052 Å2 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.073 / Net I/σ(I): 9.96
Reflection shellResolution: 2.6→2.64 Å / Num. unique obs: 2147 / CC1/2: 0.577

-
Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: GRK2

Resolution: 2.60608692764→37.1456237759 Å / SU ML: 0.3874797241 / Cross valid method: THROUGHOUT / σ(F): 1.33786888298 / Phase error: 30.7403996444
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.261883490594 1988 4.61702819453 %
Rwork0.204642341506 41070 -
obs0.207319145272 43058 98.5714939792 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 72.4782885558 Å2
Refinement stepCycle: LAST / Resolution: 2.60608692764→37.1456237759 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8160 0 23 0 8183
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002300615086038378
X-RAY DIFFRACTIONf_angle_d0.52817235237711297
X-RAY DIFFRACTIONf_chiral_restr0.04026541324991213
X-RAY DIFFRACTIONf_plane_restr0.003012968733871478
X-RAY DIFFRACTIONf_dihedral_angle_d13.36947615965072
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6061-2.67120.3796425367841310.3088464498072732X-RAY DIFFRACTION92.8942245295
2.6712-2.74340.3401120112561400.2994779263722898X-RAY DIFFRACTION98.6683988308
2.7434-2.82410.3379482077541400.2992479127262936X-RAY DIFFRACTION98.4635083227
2.8241-2.91530.3684164538261400.27378212112885X-RAY DIFFRACTION98.6305836322
2.9153-3.01940.3788391826981420.276654762032937X-RAY DIFFRACTION98.9395886889
3.0194-3.14020.3343540685131430.2654269595162944X-RAY DIFFRACTION98.8472622478
3.1402-3.28310.2968185002181410.2444562347072925X-RAY DIFFRACTION98.9351403679
3.2831-3.45610.3115318475451440.2316893573332936X-RAY DIFFRACTION99.1309945285
3.4561-3.67240.2856098491561420.2151260788312958X-RAY DIFFRACTION99.104859335
3.6724-3.95570.250841196761430.1918144371832930X-RAY DIFFRACTION99.2571059432
3.9557-4.35320.2603201055441440.1725914679762971X-RAY DIFFRACTION99.3620414673
4.3532-4.98180.1902656314841440.1577038224592973X-RAY DIFFRACTION99.4893073731
4.9818-6.27170.2537077952581460.1930965300473001X-RAY DIFFRACTION99.4627054362
6.2717-37.1440.1895192262211480.1574004885913044X-RAY DIFFRACTION98.8847583643
Refinement TLS params.Method: refined / Origin x: -9.87793689179 Å / Origin y: 13.7000030771 Å / Origin z: 29.03458561 Å
111213212223313233
T0.393459020402 Å20.00257109686944 Å2-0.0276642037721 Å2-0.319144869901 Å2-0.0294874432779 Å2--0.356168860311 Å2
L0.583330258327 °2-0.20097275471 °20.706326175375 °2-0.474732029453 °2-0.53583572711 °2--2.06536813644 °2
S0.196562180134 Å °-0.0489905511632 Å °-0.139311157308 Å °0.0215175371606 Å °-0.0159972007522 Å °0.0163900680499 Å °0.385851971321 Å °0.107855449429 Å °-0.156146145621 Å °
Refinement TLS groupSelection details: all

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more