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- PDB-7vkt: cryo-EM structure of LTB4-bound BLT1 in complex with Gi protein -

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Basic information

Entry
Database: PDB / ID: 7vkt
Titlecryo-EM structure of LTB4-bound BLT1 in complex with Gi protein
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Leukotriene B4 receptor 1
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR
Function / homology
Function and homology information


leukotriene B4 receptor activity / leukotriene receptor activity / Leukotriene receptors / G protein-coupled peptide receptor activity / plasma membrane => GO:0005886 / Adenylate cyclase inhibitory pathway / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding ...leukotriene B4 receptor activity / leukotriene receptor activity / Leukotriene receptors / G protein-coupled peptide receptor activity / plasma membrane => GO:0005886 / Adenylate cyclase inhibitory pathway / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / muscle contraction / Regulation of insulin secretion / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / inflammatory response / cell cycle / immune response / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / nucleotide binding / GTPase activity / centrosome / synapse / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Leukotriene B4 receptor / Leukotriene B4 type 1 receptor / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. ...Leukotriene B4 receptor / Leukotriene B4 type 1 receptor / G-protein alpha subunit, group I / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / 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 / 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) / 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 / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-8IO / LEUKOTRIENE B4 / CHOLESTEROL HEMISUCCINATE / 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 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Leukotriene B4 receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsHe, Y. / Wang, N.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32070048 China
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis of leukotriene B4 receptor 1 activation.
Authors: Na Wang / Xinheng He / Jing Zhao / Hualiang Jiang / Xi Cheng / Yu Xia / H Eric Xu / Yuanzheng He /
Abstract: Leukotriene B4 receptor 1 (BLT1) plays crucial roles in the acute inflammatory responses and is a valuable target for anti-inflammation treatment, however, the mechanism by which leukotriene B4 (LTB4) ...Leukotriene B4 receptor 1 (BLT1) plays crucial roles in the acute inflammatory responses and is a valuable target for anti-inflammation treatment, however, the mechanism by which leukotriene B4 (LTB4) activates receptor remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structure of the LTB4 -bound human BLT1 in complex with a G protein in an active conformation at resolution of 2.91 Å. In combination of molecule dynamics (MD) simulation, docking and site-directed mutagenesis, our structure reveals that a hydrogen-bond network of water molecules and key polar residues is the key molecular determinant for LTB4 binding. We also find that the displacement of residues M101 and I271 to the center of receptor, which unlock the ion lock of the lower part of pocket, is the key mechanism of receptor activation. In addition, we reveal a binding site of phosphatidylinositol (PI) and discover that the widely open ligand binding pocket may contribute the lack of specificity and efficacy for current BLT1-targeting drug design. Taken together, our structural analysis provides a scaffold for understanding BLT1 activation and a rational basis for designing anti-leukotriene drugs.
History
DepositionOct 1, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

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Assembly

Deposited unit
A: Leukotriene B4 receptor 1
B: Guanine nucleotide-binding protein G(i) subunit alpha-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)153,32911
Polymers150,2085
Non-polymers3,1206
Water1267
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1 / Mutation: S47N/G203A/E245A/A326S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: P63096
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37915.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: P62873
#4: 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 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: P59768

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Protein / Antibody , 2 types, 2 molecules AE

#1: Protein Leukotriene B4 receptor 1 / LTB4-R 1 / LTB4-R1 / Chemoattractant receptor-like 1 / G-protein coupled receptor 16 / P2Y ...LTB4-R 1 / LTB4-R1 / Chemoattractant receptor-like 1 / G-protein coupled receptor 16 / P2Y purinoceptor 7 / P2Y7


Mass: 37740.496 Da / Num. of mol.: 1 / Mutation: L106W/A196I/C287F/S310A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LTB4R, BLT, BLT1, BLTR, CMKRL1, GPR16, P2RY7 / Production host: Insect BA phytoplasma (bacteria) / References: UniProt: Q15722
#5: Antibody scFv16


Mass: 26277.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Insect BA phytoplasma (bacteria)

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Non-polymers , 4 types, 13 molecules

#6: Chemical ChemComp-LTB / LEUKOTRIENE B4


Mass: 336.466 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H32O4
#7: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C31H50O4
#8: Chemical ChemComp-8IO / [(2R)-2-[(Z)-hexadec-9-enoyl]oxy-3-[oxidanyl-[(2S,3R,5R,6S)-2,3,4,5,6-pentakis(oxidanyl)cyclohexyl]oxy-phosphoryl]oxy-propyl] octadecanoate


Mass: 837.069 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C43H81O13P
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 3D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: BLT1/Gi complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Insect BA phytoplasma (bacteria)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2300 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM diffractionCamera length: 800 mm
EM diffraction shellResolution: 3→5.5 Å / Fourier space coverage: 93.2 % / Multiplicity: 2.5 / Num. of structure factors: 244 / Phase residual: 13.5 °
EM diffraction statsFourier space coverage: 90.3 % / High resolution: 2.83 Å / Num. of intensities measured: 1590 / Num. of structure factors: 325 / Phase error rejection criteria: 20 / Rmerge: 0.198

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameCategory
7RELIONmodel fitting
9PHENIXmodel refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 450000 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Atomic model buildingPDB-ID: 6VMS

6vms


Pdb chain-ID: A
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039279
ELECTRON MICROSCOPYf_angle_d0.63912569
ELECTRON MICROSCOPYf_dihedral_angle_d11.3011340
ELECTRON MICROSCOPYf_chiral_restr0.0441433
ELECTRON MICROSCOPYf_plane_restr0.0041569

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