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- EMDB-61597: Cryo-EM structure of the DS-3801b-Motilin receptor-Gq protein complex -

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Entry
Database: EMDB / ID: EMD-61597
TitleCryo-EM structure of the DS-3801b-Motilin receptor-Gq protein complex
Map data
Sample
  • Complex: The DS-3801b-Motilin receptor-Gq protein complex
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: ScFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Motilin receptor
  • Ligand: CHOLESTEROL
  • Ligand: 4-[3-(hydroxymethyl)phenoxy]-~{N}-methyl-~{N}-[3-methyl-4-[[(3~{S})-3-methylpiperazin-1-yl]methyl]phenyl]cyclohexane-1-carboxamide
  • Ligand: water
KeywordsCryo-EM / GPCR / Motilin receptor / DS-3801b / macrolide antibiotics / Gq / complex / SIGNALING PROTEIN
Function / homology
Function and homology information


G protein-coupled peptide receptor activity / hormone binding / Peptide ligand-binding receptors / 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-coupled acetylcholine receptor signaling pathway / G-protein activation ...G protein-coupled peptide receptor activity / hormone binding / Peptide ligand-binding receptors / 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-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 / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Growth hormone secretagogue receptor/motilin receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / G protein beta WD-40 repeat protein ...Growth hormone secretagogue receptor/motilin receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / G protein beta WD-40 repeat protein / 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. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Motilin 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
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.57 Å
AuthorsXu HE / You C / Jiang Y
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
National Natural Science Foundation of China (NSFC)82121005 China
CitationJournal: Cell Rep / Year: 2025
Title: Decoding the structural basis of ligand recognition and biased signaling in the motilin receptor.
Authors: Chongzhao You / Mengting Jiang / Tianyu Gao / Zining Zhu / Xinheng He / Youwei Xu / Yuan Gao / Yi Jiang / H Eric Xu /
Abstract: The motilin receptor (MTLR) is a key target for treating gastrointestinal (GI) disorders like gastroparesis, yet developing effective agonists remains challenging due to drug tolerance and signaling ...The motilin receptor (MTLR) is a key target for treating gastrointestinal (GI) disorders like gastroparesis, yet developing effective agonists remains challenging due to drug tolerance and signaling bias. We present cryoelectron microscopy (cryo-EM) structures of MTLR bound to azithromycin, a macrolide antibiotic, and DS-3801b, a non-macrolide agonist. Distinct ligand recognition mechanisms are revealed, with azithromycin binding deeply within the orthosteric pocket and DS-3801b adopting a special clamp-like conformation stabilized by a water molecule. We also highlight the critical role of extracellular loop 2 (ECL2) in ligand specificity and signaling pathway activation, affecting both G-protein and β-arrestin signaling. Additionally, the "DRS" motif and interactions around transmembranes 6/7 (TM6/7) are identified as key drivers of signaling selectivity. These findings offer insights into the structural dynamics of MTLR, laying the groundwork for the rational design of next-generation GI prokinetic drugs with enhanced efficacy and safety.
History
DepositionSep 20, 2024-
Header (metadata) releaseMay 28, 2025-
Map releaseMay 28, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_61597.png

Downloads & links

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Map

FileDownload / File: emd_61597.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 256 pix.
= 186.88 Å		0.73 Å/pix.
x 256 pix.
= 186.88 Å		0.73 Å/pix.
x 256 pix.
= 186.88 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.21
Minimum - Maximum-0.96114075 - 1.83458
Average (Standard dev.)0.002611151 (±0.060197726)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 186.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61597_half_map_1.map
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Half map: #1

Fileemd_61597_half_map_2.map
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Sample components

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Entire : The DS-3801b-Motilin receptor-Gq protein complex

EntireName: The DS-3801b-Motilin receptor-Gq protein complex
Components
  • Complex: The DS-3801b-Motilin receptor-Gq protein complex
    • Protein or peptide: Guanine nucleotide-binding protein G(q) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: ScFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Motilin receptor
  • Ligand: CHOLESTEROL
  • Ligand: 4-[3-(hydroxymethyl)phenoxy]-~{N}-methyl-~{N}-[3-methyl-4-[[(3~{S})-3-methylpiperazin-1-yl]methyl]phenyl]cyclohexane-1-carboxamide
  • Ligand: water

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Supramolecule #1: The DS-3801b-Motilin receptor-Gq protein complex

SupramoleculeName: The DS-3801b-Motilin receptor-Gq 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(q) subunit alpha

MacromoleculeName: Guanine nucleotide-binding protein G(q) subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.724383 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTSGIFETK FQVDKVNFHM FDVGAQRDER RKWIQCFNDV TAIIFVVDSS DYNRLQEALN DF KSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRKEFVDIST ASG DGRHIC YPHFTCSVDT ENARRIFNDC KDIILQMNLR EYNLV

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Macromolecule #2: 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: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.915496 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String:
MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN

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

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Macromolecule #3: ScFv16

MacromoleculeName: ScFv16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.277299 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL

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Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.729947 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
ASNNTASIAQ ARKLVEQLKM EANIDRIKVS KAAADLMAYC EAHAKEDPLL TPVPASENPF REKKFFCAIL

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

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Macromolecule #5: Motilin receptor

MacromoleculeName: Motilin receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.392184 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGSPWNGSDG PEGAREPPWP ALPPCDERRC SPFPLGALVP VTAVCLCLFV VGVSGNVVTV MLIGRYRDMR TTTNLYLGSM AVSDLLILL GLPFDLYRLW RSRPWVFGPL LCRLSLYVGE GCTYATLLHM TALSVERYLA ICRPLRARVL VTRRRVRALI A VLWAVALL ...String:
MGSPWNGSDG PEGAREPPWP ALPPCDERRC SPFPLGALVP VTAVCLCLFV VGVSGNVVTV MLIGRYRDMR TTTNLYLGSM AVSDLLILL GLPFDLYRLW RSRPWVFGPL LCRLSLYVGE GCTYATLLHM TALSVERYLA ICRPLRARVL VTRRRVRALI A VLWAVALL SAGPFLFLVG VEQDPGISVV PGLNGTARIA SSPLASSPPL WLSRAPPPSP PSGPETAEAA ALFSRECRPS PA QLGALRV MLWVTTAYFF LPFLCLSILY GLIGRELWSS RRPLRGPAAS GRERGHRQTV RVLLVVVLAF IICWLPFHVG RII YINTED SRMMYFSQYF NIVALQLFYL SASINPILYN LISKKYRAAA FKLLLARKSR PRGFHRSRDT AGEVAGDTGG DTVG YTETS ANVKTMG

UniProtKB: Motilin receptor

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #7: 4-[3-(hydroxymethyl)phenoxy]-~{N}-methyl-~{N}-[3-methyl-4-[[(3~{S...

MacromoleculeName: 4-[3-(hydroxymethyl)phenoxy]-~{N}-methyl-~{N}-[3-methyl-4-[[(3~{S})-3-methylpiperazin-1-yl]methyl]phenyl]cyclohexane-1-carboxamide
type: ligand / ID: 7 / Number of copies: 1 / Formula: A1L4H
Molecular weightTheoretical: 465.628 Da

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Macromolecule #8: water

MacromoleculeName: water / type: ligand / ID: 8 / Number of copies: 6 / 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

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 30.0 µm / Nominal defocus min: 5.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.57 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 478048
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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