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- EMDB-25399: Molecular mechanism of the the wake-promoting agent TAK-925 -

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Basic information

Entry
Database: EMDB / ID: EMD-25399
TitleMolecular mechanism of the the wake-promoting agent TAK-925
Map dataMolecular mechanism of the the wake-promoting agent TAK-925
Sample
  • Complex: Human orexin receptor 2 - G protein complex
    • Protein or peptide: a modified 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: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Hypocretin receptor type 2
  • Ligand: methyl (2R,3S)-3-[(methanesulfonyl)amino]-2-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate
  • Ligand: OLEIC ACID
Function / homology
Function and homology information


circadian sleep/wake cycle process / orexin receptor activity / feeding behavior / 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 activation / G protein-coupled acetylcholine receptor signaling pathway ...circadian sleep/wake cycle process / orexin receptor activity / feeding behavior / 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 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 / 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 / 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 / sensory perception of taste / GPER1 signaling / 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) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / 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
Orexin receptor 2 / Orexin receptor type 2 / Orexin receptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 ...Orexin receptor 2 / Orexin receptor type 2 / Orexin receptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
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 / Orexin receptor type 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYin J / Chapman K / Lian P / De Brabander JK / Rosenbaum DM
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)5R01NS103939-03 United States
CitationJournal: Nat Commun / Year: 2022
Title: Molecular mechanism of the wake-promoting agent TAK-925.
Authors: Jie Yin / Yanyong Kang / Aaron P McGrath / Karen Chapman / Megan Sjodt / Eiji Kimura / Atsutoshi Okabe / Tatsuki Koike / Yuhei Miyanohana / Yuji Shimizu / Rameshu Rallabandi / Peng Lian / ...Authors: Jie Yin / Yanyong Kang / Aaron P McGrath / Karen Chapman / Megan Sjodt / Eiji Kimura / Atsutoshi Okabe / Tatsuki Koike / Yuhei Miyanohana / Yuji Shimizu / Rameshu Rallabandi / Peng Lian / Xiaochen Bai / Mack Flinspach / Jef K De Brabander / Daniel M Rosenbaum /
Abstract: The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic ...The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic strategy for insomnia drugs, and agonism of OXR is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OXR had been considered 'undruggable.' We harness cryo-electron microscopy of OXR-G protein complexes to determine how the first clinically tested OXR agonist TAK-925 can activate OXR in a highly selective manner. Two structures of TAK-925-bound OXR with either a G mimetic or G reveal that TAK-925 binds at the same site occupied by antagonists, yet interacts with the transmembrane helices to trigger activating microswitches. Our structural and mutagenesis data show that TAK-925's selectivity is mediated by subtle differences between OX and OX receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OXR's coupling selectivity for G signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OXR agonists for narcolepsy and other circadian disorders.
History
DepositionNov 8, 2021-
Header (metadata) releaseJun 8, 2022-
Map releaseJun 8, 2022-
UpdateJun 8, 2022-
Current statusJun 8, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25399.png

Downloads & links

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Map

FileDownload / File: emd_25399.map.gz / Format: CCP4 / Size: 35.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMolecular mechanism of the the wake-promoting agent TAK-925
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.1415578 - 0.21905038
Average (Standard dev.)-1.0408633e-05 (±0.006725707)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions210210210
Spacing210210210
CellA=B=C: 226.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Human orexin receptor 2 - G protein complex

EntireName: Human orexin receptor 2 - G protein complex
Components
  • Complex: Human orexin receptor 2 - G protein complex
    • Protein or peptide: a modified 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: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Hypocretin receptor type 2
  • Ligand: methyl (2R,3S)-3-[(methanesulfonyl)amino]-2-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate
  • Ligand: OLEIC ACID

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Supramolecule #1: Human orexin receptor 2 - G protein complex

SupramoleculeName: Human orexin receptor 2 - G protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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Macromolecule #1: a modified Guanine nucleotide-binding protein G(q) subunit alpha

MacromoleculeName: a modified 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: 27.638461 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTLSAEDK AAVERSKMID RNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHTSG IFETKFQVDK VNFHMFDVGG QRDERRKWI QCFNDVTAII FVVDSSDYNR LQEALNDFKS IWNNRWLRTI SVILFLNKQD LLAEKVLAGK SKIEDYFPEF A RYTTPEDA ...String:
MGSTLSAEDK AAVERSKMID RNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHTSG IFETKFQVDK VNFHMFDVGG QRDERRKWI QCFNDVTAII FVVDSSDYNR LQEALNDFKS IWNNRWLRTI SVILFLNKQD LLAEKVLAGK SKIEDYFPEF A RYTTPEDA TPEPGEDPRV TRAKYFIRKE FVDISTASGD GRHICYPHFT CAVDTENARR IFNDCKDIIL QMNLREYNLV

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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: 37.41693 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.137474 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MGHHHHHHHH GGASNNTASI AQARKLVEQL KMEANIDRIK VSKAAADLMA YCEAHAKEDP LLTPVPASEN PFREKKFFCA IL

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Macromolecule #4: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.784896 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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 #5: Hypocretin receptor type 2

MacromoleculeName: Hypocretin receptor type 2 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.848031 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGTKLEDSPP CRNWSSASEL NETQEPFLNP TDYDDEEFLR YLWREYLHPK EYEWVLIAGY IIVFVVALIG NVLVCVAVWK NHHMRTVTN YFIVNLSLAD VLVTITCLPA TLVVDITETW FFGQSLCKVI PYLQTVSVSV SVLTLSCIAL DRWYAICHPL M FKSTAKRA ...String:
MGTKLEDSPP CRNWSSASEL NETQEPFLNP TDYDDEEFLR YLWREYLHPK EYEWVLIAGY IIVFVVALIG NVLVCVAVWK NHHMRTVTN YFIVNLSLAD VLVTITCLPA TLVVDITETW FFGQSLCKVI PYLQTVSVSV SVLTLSCIAL DRWYAICHPL M FKSTAKRA RNSIVIIWIV SCIIMIPQAI VMECSTVFPG LANKTTLFTV CDERWGGEIY PKMYHICFFL VTYMAPLCLM VL AYLQIFR KLWCRQIPGT SSVVQRKWKP LQPVSQPRGP GQPTKSRMSA VAAEIKQIRA RRKTARMLMV VLLVFAICYL PIS ILNVLK RVFGMFAHTE DRETVYAWFT FSHWLVYANS AANPIIYNFL SGKFREEFKA AFSCCCLGVH HRQEDRLTRG RTST ESRKS LT

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Macromolecule #6: methyl (2R,3S)-3-[(methanesulfonyl)amino]-2-({[(1s,4S)-4-phenylcy...

MacromoleculeName: methyl (2R,3S)-3-[(methanesulfonyl)amino]-2-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate
type: ligand / ID: 6 / Number of copies: 1 / Formula: A6F
Molecular weightTheoretical: 424.554 Da
Chemical component information

ChemComp-A6F:
methyl (2R,3S)-3-[(methanesulfonyl)amino]-2-({[(1s,4S)-4-phenylcyclohexyl]oxy}methyl)piperidine-1-carboxylate

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Macromolecule #7: OLEIC ACID

MacromoleculeName: OLEIC ACID / type: ligand / ID: 7 / Number of copies: 4 / Formula: OLA
Molecular weightTheoretical: 282.461 Da
Chemical component information

ChemComp-OLA:
OLEIC ACID / Oleic acid

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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 TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE / Details: ab initial model generated by Relion
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0.1)
Final 3D classificationSoftware - Name: RELION (ver. 3.0.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0.1)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0.1) / Number images used: 155322
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6ddf

Output model

PDB-7sr8:
Molecular mechanism of the the wake-promoting agent TAK-925

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