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- PDB-7sus: Crystal structure of Apelin receptor in complex with small molecule -

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Basic information

Entry
Database: PDB / ID: 7sus
TitleCrystal structure of Apelin receptor in complex with small molecule
ComponentsApelin receptor, with Rubredoxin insertion
KeywordsMEMBRANE PROTEIN / GPCR / Class A GPCR / small molecule / Apelin receptor
Function / homology
Function and homology information


apelin receptor activity / apelin receptor signaling pathway / regulation of gap junction assembly / positive regulation of inhibitory G protein-coupled receptor phosphorylation / vascular associated smooth muscle cell differentiation / atrioventricular valve development / regulation of body fluid levels / venous blood vessel development / alkane catabolic process / positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis ...apelin receptor activity / apelin receptor signaling pathway / regulation of gap junction assembly / positive regulation of inhibitory G protein-coupled receptor phosphorylation / vascular associated smooth muscle cell differentiation / atrioventricular valve development / regulation of body fluid levels / venous blood vessel development / alkane catabolic process / positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / endocardial cushion formation / C-C chemokine receptor activity / coronary vasculature development / C-C chemokine binding / adult heart development / vasculature development / negative regulation of cAMP-mediated signaling / aorta development / ventricular septum morphogenesis / blood vessel development / heart looping / vasculogenesis / gastrulation / Peptide ligand-binding receptors / neurogenesis / cell chemotaxis / positive regulation of release of sequestered calcium ion into cytosol / G protein-coupled receptor activity / calcium-mediated signaling / brain development / positive regulation of angiogenesis / signaling receptor activity / heart development / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / regulation of gene expression / angiogenesis / electron transfer activity / iron ion binding / immune response / G protein-coupled receptor signaling pathway / external side of plasma membrane / negative regulation of gene expression / plasma membrane
Similarity search - Function
Apelin receptor / Rubredoxin / Rubredoxin, iron-binding site / Rubredoxin signature. / Rubredoxin domain / Rubredoxin / Rubredoxin-like domain / Rubredoxin-like domain profile. / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like ...Apelin receptor / Rubredoxin / Rubredoxin, iron-binding site / Rubredoxin signature. / Rubredoxin domain / Rubredoxin / Rubredoxin-like domain / Rubredoxin-like domain profile. / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Chem-8EH / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / Rubredoxin / Apelin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Clostridium pasteurianum (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsXu, F. / Yue, Y. / Liu, L.E. / Han, G.W. / Hanson, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Structural insight into apelin receptor-G protein stoichiometry.
Authors: Yang Yue / Lier Liu / Li-Jie Wu / Yiran Wu / Ling Wang / Fei Li / Junlin Liu / Gye-Won Han / Bo Chen / Xi Lin / Rebecca L Brouillette / Émile Breault / Jean-Michel Longpré / Songting Shi / ...Authors: Yang Yue / Lier Liu / Li-Jie Wu / Yiran Wu / Ling Wang / Fei Li / Junlin Liu / Gye-Won Han / Bo Chen / Xi Lin / Rebecca L Brouillette / Émile Breault / Jean-Michel Longpré / Songting Shi / Hui Lei / Philippe Sarret / Raymond C Stevens / Michael A Hanson / Fei Xu /
Abstract: The technique of cryogenic-electron microscopy (cryo-EM) has revolutionized the field of membrane protein structure and function with a focus on the dominantly observed molecular species. This report ...The technique of cryogenic-electron microscopy (cryo-EM) has revolutionized the field of membrane protein structure and function with a focus on the dominantly observed molecular species. This report describes the structural characterization of a fully active human apelin receptor (APJR) complexed with heterotrimeric G protein observed in both 2:1 and 1:1 stoichiometric ratios. We use cryo-EM single-particle analysis to determine the structural details of both species from the same sample preparation. Protein preparations, in the presence of the endogenous peptide ligand ELA or a synthetic small molecule, both demonstrate these mixed stoichiometric states. Structural differences in G protein engagement between dimeric and monomeric APJR suggest a role for the stoichiometry of G protein-coupled receptor- (GPCR-)G protein coupling on downstream signaling and receptor pharmacology. Furthermore, a small, hydrophobic dimer interface provides a starting framework for additional class A GPCR dimerization studies. Together, these findings uncover a mechanism of versatile regulation through oligomerization by which GPCRs can modulate their signaling.
History
DepositionNov 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Apelin receptor, with Rubredoxin insertion
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,3844
Polymers46,4371
Non-polymers9483
Water181
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)163.010, 44.560, 79.680
Angle α, β, γ (deg.)90.000, 115.620, 90.000
Int Tables number5
Space group name H-MC121
DetailsThe authors state that the biological oligomeric state is unknown.

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Components

#1: Protein Apelin receptor, with Rubredoxin insertion


Mass: 46436.613 Da / Num. of mol.: 1 / Mutation: V117A,E174C,T177N,M217C,I250C,C325L,C326M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Clostridium pasteurianum (bacteria)
Gene: APLNR, AGTRL1, APJ / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P35414, UniProt: P00268
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-8EH / (1R,2S)-N-[4-(2,6-dimethoxyphenyl)-5-(6-methylpyridin-2-yl)-1,2,4-triazol-3-yl]-1-(5-methylpyrimidin-2-yl)-1-oxidanyl-propane-2-sulfonamide


Mass: 525.580 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H27N7O5S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H40O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Sequence detailsRubredoxin from a Clostridium species is inserted in the cytoplasmic region between helices 5 and 6

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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: 2.81 Å3/Da / Density % sol: 56.22 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 100 mM MES pH 6.1, 26% PEG500 DME, 125 mM MgCl2, 100 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 19, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→42.93 Å / Num. obs: 13301 / % possible obs: 92.3 % / Redundancy: 4.4 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 5.9
Reflection shellResolution: 2.7→2.85 Å / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1636

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5VBL, 1IRO

5vbl

1iro


Resolution: 2.7→30 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.891 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.755 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.697 / SU Rfree Blow DPI: 0.335 / SU Rfree Cruickshank DPI: 0.344
RfactorNum. reflection% reflectionSelection details
Rfree0.274 645 4.85 %RANDOM
Rwork0.252 ---
obs0.253 13292 91.7 %-
Displacement parametersBiso max: 274.36 Å2 / Biso mean: 129.6 Å2 / Biso min: 30 Å2
Baniso -1Baniso -2Baniso -3
1--0.4425 Å20 Å2-8.1638 Å2
2---6.5 Å20 Å2
3---6.9425 Å2
Refinement stepCycle: final / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2686 0 51 1 2738
Biso mean--152.44 51.23 -
Num. residues----347
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d878SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes39HARMONIC2
X-RAY DIFFRACTIONt_gen_planes418HARMONIC5
X-RAY DIFFRACTIONt_it2819HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion368SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3076SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2819HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3859HARMONIC20.83
X-RAY DIFFRACTIONt_omega_torsion1.42
X-RAY DIFFRACTIONt_other_torsion19.96
LS refinement shellResolution: 2.7→2.92 Å / Rfactor Rfree error: 0 / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.217 108 4.54 %
Rwork0.209 2273 -
all0.21 2381 -
obs--80.79 %
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)
10.85950.3694-1.4761.73780.59212.4672-0.0045-0.31830.1050.11950.0486-0.203-0.07510.1427-0.04420.14090.08420.20990.0582-0.0888-0.2064-39.43746.796236.7906
20.48960.5554-0.87931.4281.03611.53810.012-0.0196-0.01670.0081-0.00690.037-0.0158-0.0324-0.00510.24290.05150.16330.0153-0.1007-0.2337-44.1008-16.9781-0.7842
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|31 - A|336 A|1102 - A|1103 }A31 - 336
2X-RAY DIFFRACTION1{ A|31 - A|336 A|1102 - A|1103 }A1102 - 1103
3X-RAY DIFFRACTION2{ A|1001 - A|1101 }A1001 - 1101

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