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- EMDB-25034: FH210 bound Mu Opioid Receptor-Gi Protein Complex -

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Entry
Database: EMDB / ID: EMD-25034
TitleFH210 bound Mu Opioid Receptor-Gi Protein Complex
Map dataFH210 bound mu opioid receptor in complex with Gi and scFv
Sample
  • Complex: FH210 bound Mu Opioid Receptor-Gi Protein Complex
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Mu-type opioid receptor
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: scFv16
  • Ligand: (2E)-N-[(2S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-(naphthalen-1-yl)prop-2-enamide
  • Ligand: water
KeywordsGPCR / MEMBRANE PROTEIN
Function / homology
Function and homology information


Opioid Signalling / spine apparatus / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / Peptide ligand-binding receptors / adenylate cyclase-inhibiting opioid receptor signaling pathway / positive regulation of appetite / G-protein activation / G protein-coupled opioid receptor activity ...Opioid Signalling / spine apparatus / beta-endorphin receptor activity / morphine receptor activity / negative regulation of Wnt protein secretion / Peptide ligand-binding receptors / adenylate cyclase-inhibiting opioid receptor signaling pathway / positive regulation of appetite / G-protein activation / G protein-coupled opioid receptor activity / negative regulation of luteinizing hormone secretion / G protein-coupled opioid receptor signaling pathway / sperm ejaculation / G alpha (i) signalling events / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / negative regulation of nitric oxide biosynthetic process / negative regulation of cAMP-mediated signaling / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / neuropeptide binding / regulation of NMDA receptor activity / positive regulation of neurogenesis / eating behavior / negative regulation of cytosolic calcium ion concentration / transmission of nerve impulse / social behavior / neuropeptide signaling pathway / G-protein alpha-subunit binding / T cell migration / D2 dopamine receptor binding / voltage-gated calcium channel activity / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / GABA-ergic synapse / cellular response to forskolin / positive regulation of gluconeogenesis / regulation of mitotic spindle organization / dendrite membrane / sensory perception of pain / presynaptic modulation of chemical synaptic transmission / dendrite cytoplasm / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / excitatory postsynaptic potential / Regulation of insulin secretion / locomotory behavior / G protein-coupled receptor binding / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / adenylate cyclase-modulating G protein-coupled receptor 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-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / response to peptide hormone / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / 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 / presynaptic membrane / Ca2+ pathway / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events
Similarity search - Function
Mu opioid receptor / Opioid receptor / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. ...Mu opioid receptor / Opioid receptor / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / 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
Mu-type opioid receptor / 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
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsWang H / Kobilka B
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) United States
CitationJournal: Angew Chem Int Ed Engl / Year: 2022
Title: Structure-Based Evolution of G Protein-Biased μ-Opioid Receptor Agonists.
Authors: Haoqing Wang / Florian Hetzer / Weijiao Huang / Qianhui Qu / Justin Meyerowitz / Jonas Kaindl / Harald Hübner / Georgios Skiniotis / Brian K Kobilka / Peter Gmeiner /
Abstract: The μ-opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β-arrestin recruitment. μOR agonists ...The μ-opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β-arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μOR agonist. Here we report the cryoEM structure of PZM21 bound μOR in complex with G protein. Structure-based evolution led to multiple PZM21 analogs with more pronounced G protein bias and increased lipophilicity to improve CNS penetration. Among them, FH210 shows extremely low potency and efficacy for arrestin recruitment. We further determined the cryoEM structure of FH210 bound to μOR in complex with G protein and confirmed its expected binding pose. The structural and pharmacological studies reveal a potential mechanism to reduce β-arrestin recruitment by the μOR, and hold promise for developing next-generation analgesics with fewer adverse effects.
History
DepositionSep 28, 2021-
Header (metadata) releaseApr 20, 2022-
Map releaseApr 20, 2022-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25034.png

Downloads & links

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Map

FileDownload / File: emd_25034.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFH210 bound mu opioid receptor in complex with Gi and scFv
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.87 Å/pix.
x 256 pix.
= 222.106 Å		0.87 Å/pix.
x 256 pix.
= 222.106 Å		0.87 Å/pix.
x 256 pix.
= 222.106 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8676 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.27
Minimum - Maximum-24.252051999999999 - 42.038105000000002
Average (Standard dev.)-0.000000000007172 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 222.1056 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : FH210 bound Mu Opioid Receptor-Gi Protein Complex

EntireName: FH210 bound Mu Opioid Receptor-Gi Protein Complex
Components
  • Complex: FH210 bound Mu Opioid Receptor-Gi Protein Complex
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Mu-type opioid receptor
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: scFv16
  • Ligand: (2E)-N-[(2S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-(naphthalen-1-yl)prop-2-enamide
  • Ligand: water

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Supramolecule #1: FH210 bound Mu Opioid Receptor-Gi Protein Complex

SupramoleculeName: FH210 bound Mu Opioid Receptor-Gi Protein Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.671102 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...String:
PGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #3: Mu-type opioid receptor

MacromoleculeName: Mu-type opioid receptor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 39.995105 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: NISDCSDPLA PASCSPAPGS WLNLSHVDGN QSDPCGPNRT GLGENLYFQG SHSLCPQTGS PSMVTAITIM ALYSIVCVVG LFGNFLVMY VIVRYTKMKT ATNIYIFNLA LADALATSTL PFQSVNYLMG TWPFGNILCK IVISIDYYNM FTSIFTLCTM S VDRYIAVC ...String:
NISDCSDPLA PASCSPAPGS WLNLSHVDGN QSDPCGPNRT GLGENLYFQG SHSLCPQTGS PSMVTAITIM ALYSIVCVVG LFGNFLVMY VIVRYTKMKT ATNIYIFNLA LADALATSTL PFQSVNYLMG TWPFGNILCK IVISIDYYNM FTSIFTLCTM S VDRYIAVC HPVKALDFRT PRNAKIVNVC NWILSSAIGL PVMFMATTKY RQGSIDCTLT FSHPTWYWEN LLKICVFIFA FI MPVLIIT VCYGLMILRL KSVRMLSGSK EKDRNLRRIT RMVLVVVAVF IVCWTPIHIY VIIKALITIP ETTFQTVSWH FCI ALGYTN SCLNPVLYAF LDENFKRCFR EFCIPTSSTI

UniProtKB: Mu-type opioid receptor

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Macromolecule #4: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.415031 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.784896 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAAHHHHHH HH

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Macromolecule #6: (2E)-N-[(2S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-(naph...

MacromoleculeName: (2E)-N-[(2S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-(naphthalen-1-yl)prop-2-enamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: 8RI
Molecular weightTheoretical: 374.475 Da
Chemical component information

ChemComp-8RI:
(2E)-N-[(2S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-(naphthalen-1-yl)prop-2-enamide

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 66.75 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 661174
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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