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Yorodumi- EMDB-39009: positive allosteric modulator(BMS986187)-bound delta-opioid recep... -
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Basic information
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| Title | positive allosteric modulator(BMS986187)-bound delta-opioid receptor-Gi complex | |||||||||
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Keywords | positive allosteric modulator / BMS986187 / delta-opioid receptor / allosteric agonism / allosteric opioid analgesics / MEMBRANE PROTEIN | |||||||||
| Function / homology | Function and homology informationG protein-coupled enkephalin receptor activity / spine apparatus / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / receptor serine/threonine kinase binding / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste ...G protein-coupled enkephalin receptor activity / spine apparatus / G protein-coupled opioid receptor activity / G protein-coupled opioid receptor signaling pathway / receptor serine/threonine kinase binding / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to toxic substance / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / neuropeptide binding / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / Thrombin signalling through proteinase activated receptors (PARs) / eating behavior / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / spectrin binding / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / regulation of calcium ion transport / alkylglycerophosphoethanolamine phosphodiesterase activity / photoreceptor outer segment / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuronal dense core vesicle / negative regulation of protein-containing complex assembly / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / cardiac muscle cell apoptotic process / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / photoreceptor inner segment / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / dendrite membrane / cellular response to forskolin / axon terminus / Peptide ligand-binding receptors / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / regulation of mitochondrial membrane potential / adult locomotory behavior / response to nicotine / Regulation of insulin secretion / neuropeptide signaling pathway / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / postsynaptic density membrane / response to peptide hormone / cellular response to growth factor stimulus / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / GDP binding / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production Similarity search - Function | |||||||||
| Biological species | Homo sapiens (human) / ![]() ![]() | |||||||||
| Method | single particle reconstruction / cryo EM / Resolution: 2.97 Å | |||||||||
Authors | Luo P / Xu Y / Wang Y / Zhuang Y / Xu HE | |||||||||
| Funding support | China, 2 items
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Citation | Journal: Sci Adv / Year: 2026Title: Structure-based design of an opioid receptor modulator for enhanced morphine analgesia. Authors: Yue Wang / Ping Luo / Haiyan Xu / Li Zhan / Kensuke Sakamoto / Mingyu Li / Jing Wang / Xi-Ping Huang / Jianhui Zhou / Tao Liu / Yanrui Suo / Wenjia Fan / Xinheng He / Youwei Xu / Yongjie Cai ...Authors: Yue Wang / Ping Luo / Haiyan Xu / Li Zhan / Kensuke Sakamoto / Mingyu Li / Jing Wang / Xi-Ping Huang / Jianhui Zhou / Tao Liu / Yanrui Suo / Wenjia Fan / Xinheng He / Youwei Xu / Yongjie Cai / Chao Wang / Yuxi Zhao / Antao Dai / Yali Lai / Qingning Yuan / Wen Hu / Kai Wu / Dehua Yang / Xi Cheng / Xiaojie Lu / Brian Krumm / Terry Kenakin / Jian Zhang / Bryan L Roth / Zhaobing Gao / H Eric Xu / Youwen Zhuang / ![]() Abstract: The alarming rates of deaths due to opioid overdose present an urgent need for safer opioid analgesics. Positive allosteric modulators (PAMs) of opioid receptors (ORs) offer a promising approach to ...The alarming rates of deaths due to opioid overdose present an urgent need for safer opioid analgesics. Positive allosteric modulators (PAMs) of opioid receptors (ORs) offer a promising approach to enhance opioid efficacy while reducing risks of overdose. In this study, we unveil the selective mechanism of PAM modulation of the OR family through structure elucidation of the δ-opioid receptor and μ-opioid receptor (μOR) bound to orthosteric agonists and PAMs BMS986187 (BMS187) and BMS986122 (BMS122). In addition, we uncovered an unexpected but conserved allosteric site across the transmembrane helices TM2 to TM4 of ORs, occupied by BMS187 but not BMS122. Leveraging these structural insights, we designed 9-(5-(4-chlorophenyl)furan-2-yl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1-xanthene-1,8(2)-dione (MPAM-15), whose αβ cooperativity factor is 33-fold higher than BMS122 and threefold higher than BMS187, indicating markedly stronger positive allosterism. Animal studies demonstrate that MPAM-15 shows excellent brain penetration and enhances morphine-induced antinociception without exacerbating respiratory depression or constipation. Molecular dynamics simulations revealed that MPAM-15 promotes and stabilizes the conformational equilibrium of μOR toward the canonical active state, providing a mechanistic basis for its enhanced allosteric potency. These discoveries substantially advance our understanding of OR allosteric mechanism and pave the way for the structure-based development of allosteric opioid analgesics. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
| Map data | emd_39009.map.gz | 6.4 MB | EMDB map data format | |
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| Header (meta data) | emd-39009-v30.xml emd-39009.xml | 26.3 KB 26.3 KB | Display Display | EMDB header |
| Images | emd_39009.png | 42 KB | ||
| Filedesc metadata | emd-39009.cif.gz | 7.8 KB | ||
| Others | emd_39009_half_map_1.map.gz emd_39009_half_map_2.map.gz | 80.8 MB 80.9 MB | ||
| Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-39009 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-39009 | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 8y71MC ![]() 8y72C ![]() 8y73C ![]() 9l60C M: atomic model generated by this map C: citing same article ( |
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| Similar structure data | Similarity search - Function & homology F&H Search |
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Links
| EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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| Related items in Molecule of the Month |
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Map
| File | Download / File: emd_39009.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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| Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
| Voxel size | X=Y=Z: 0.824 Å | ||||||||||||||||||||||||||||||||||||
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| Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
| Details | EMDB XML:
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-Supplemental data
-Half map: #2
| File | emd_39009_half_map_1.map | ||||||||||||
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| Density Histograms |
-Half map: #1
| File | emd_39009_half_map_2.map | ||||||||||||
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Sample components
-Entire : positive allosteric modulator(BMS986187)-bound delta-opioid recep...
| Entire | Name: positive allosteric modulator(BMS986187)-bound delta-opioid receptor-G complex |
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| Components |
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-Supramolecule #1: positive allosteric modulator(BMS986187)-bound delta-opioid recep...
| Supramolecule | Name: positive allosteric modulator(BMS986187)-bound delta-opioid receptor-G complex type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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| Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
| Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 40.445059 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: 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 FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
| Macromolecule | Name: 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 |
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| Source (natural) | Organism: ![]() |
| Molecular weight | Theoretical: 40.226992 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: 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 WDSFLKIWNG SSGGGGSGGG GSSGVSGWRL FKKIS UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
| Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: ![]() |
| Molecular weight | Theoretical: 7.56375 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFC UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #4: scFv16
| Macromolecule | Name: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: synthetic construct (others) |
| Molecular weight | Theoretical: 26.408492 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: MVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SAGGGGSGGG GSGGGGSADI VMTQATSSVP VTPGESVSIS C RSSKSLLH ...String: MVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SAGGGGSGGG GSGGGGSADI VMTQATSSVP VTPGESVSIS C RSSKSLLH SNGNTYLYWF LQRPGQSPQL LIYRMSNLAS GVPDRFSGSG SGTAFTLTIS RLEAEDVGVY YCMQHLEYPL TF GAGTKLE L |
-Macromolecule #5: Delta-type opioid receptor
| Macromolecule | Name: Delta-type opioid receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 57.48498 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: EPAPSAGAEL QPPLFANASD AYPSACPSAG ANASGPPGAR SASSLALAIA ITALYSAVCA VGLLGNVLVM FGIVRYTKMK TATNIYIFN LALADALATS TLPFQSAKYL METWPFGELL CKAVLSIDYY NMFTSIFTLT MMSVDRYIAV CHPVKALDFR T PAKAKLIN ...String: EPAPSAGAEL QPPLFANASD AYPSACPSAG ANASGPPGAR SASSLALAIA ITALYSAVCA VGLLGNVLVM FGIVRYTKMK TATNIYIFN LALADALATS TLPFQSAKYL METWPFGELL CKAVLSIDYY NMFTSIFTLT MMSVDRYIAV CHPVKALDFR T PAKAKLIN ICIWVLASGV GVPIMVMAVT RPRDGAVVCM LQFPSPSWYW DTVTKICVFL FAFVVPILII TVCYGLMLLR LR SVRLLSG SKEKDRSLRR ITRMVLVVVG AFVVCWAPIH IFVIVWTLVD IDRRDPLVVA ALHLCIALGY ANSSLNPVLY AFL DENFKR CFRQLCRKPC GRPDPSSFSR AREATARERV TACTPSDGPV FTLEDFVGDW EQTAAYNLDQ VLEQGGVSSL LQNL AVSVT PIQRIVRSGE NALKIDIHVI IPYEGLSADQ MAQIEEVFKV VYPVDDHHFK VILPYGTLVI DGVTPNMLNY FGRPY EGIA VFDGKKITVT GTLWNGNKII DERLITPDGS MLFRVTINS UniProtKB: Delta-type opioid receptor |
-Macromolecule #6: 3,3,6,6-tetramethyl-9-[4-[(2-methylphenyl)methoxy]phenyl]-4,5,7,9...
| Macromolecule | Name: 3,3,6,6-tetramethyl-9-[4-[(2-methylphenyl)methoxy]phenyl]-4,5,7,9-tetrahydro-2~{H}-xanthene-1,8-dione type: ligand / ID: 6 / Number of copies: 1 / Formula: A1D6B |
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| Molecular weight | Theoretical: 470.599 Da |
-Macromolecule #7: 4-[(~{S})-[(2~{R},5~{S})-2,5-dimethyl-4-prop-2-enyl-piperazin-1-y...
| Macromolecule | Name: 4-[(~{S})-[(2~{R},5~{S})-2,5-dimethyl-4-prop-2-enyl-piperazin-1-yl]-(3-methoxyphenyl)methyl]-~{N},~{N}-diethyl-benzamide type: ligand / ID: 7 / Number of copies: 1 / Formula: A1D6F |
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| Molecular weight | Theoretical: 449.628 Da |
-Experimental details
-Structure determination
| Method | cryo EM |
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Processing | single particle reconstruction |
| Aggregation state | particle |
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Sample preparation
| Buffer | pH: 7.2 |
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| Vitrification | Cryogen name: ETHANE |
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Electron microscopy
| Microscope | TFS KRIOS |
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| Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
| Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
| Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm |
| Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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About Yorodumi



Keywords
Homo sapiens (human)
Authors
China, 2 items
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Processing
FIELD EMISSION GUN
