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- EMDB-63823: Cryo-EM structure of human AC9-Gs complex (soluble domain) -

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Entry
Database: EMDB / ID: EMD-63823
TitleCryo-EM structure of human AC9-Gs complex (soluble domain)
Map datamain map
Sample
  • Complex: human AC9 in complex with GalphaS
    • Protein or peptide: Adenylate cyclase type 9,Protein M2-1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
  • Ligand: 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
  • Ligand: MAGNESIUM ION
Keywordsenzyme / MEMBRANE PROTEIN
Function / homology
Function and homology information


Adenylate cyclase activating pathway / regulation of viral transcription / symbiont-mediated activation of host NF-kappaB cascade / adenylate cyclase / cAMP biosynthetic process / adenylate cyclase activity / PKA activation / viral transcription / PKA activation in glucagon signalling / developmental growth ...Adenylate cyclase activating pathway / regulation of viral transcription / symbiont-mediated activation of host NF-kappaB cascade / adenylate cyclase / cAMP biosynthetic process / adenylate cyclase activity / PKA activation / viral transcription / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / Adenylate cyclase inhibitory pathway / regulation of insulin secretion / cellular response to glucagon stimulus / FCGR3A-mediated IL10 synthesis / bioluminescence / adenylate cyclase activator activity / trans-Golgi network membrane / transcription antitermination / generation of precursor metabolites and energy / negative regulation of inflammatory response to antigenic stimulus / bone development / virion component / platelet aggregation / cognition / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / Glucagon-type ligand receptors / sensory perception of smell / 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 / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / positive regulation of cold-induced thermogenesis / G protein activity / 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 / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / in utero embryonic development / host cell cytoplasm / intracellular signal transduction / cilium / ciliary basal body / G protein-coupled receptor signaling pathway / axon / GTPase activity / dendrite / GTP binding / host cell nucleus / structural molecule activity / signal transduction / RNA binding / extracellular exosome / zinc ion binding / ATP binding / metal ion binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Pneumovirus matrix 2-1 / Pneumovirus matrix protein 2 (M2) / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylate and Guanylate cyclase catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Guanylate cyclase domain profile. / Zinc finger, CCCH-type / Zinc finger C3H1-type profile. ...Pneumovirus matrix 2-1 / Pneumovirus matrix protein 2 (M2) / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylate and Guanylate cyclase catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Guanylate cyclase domain profile. / Zinc finger, CCCH-type / Zinc finger C3H1-type profile. / Nucleotide cyclase / G-protein alpha subunit, group S / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Protein M2-1 / Adenylate cyclase type 9 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human) / Human respiratory syncytial virus
Methodsingle particle reconstruction / cryo EM / Resolution: 2.65 Å
AuthorsSuzuki S / Nomura R / Suzuki H / Nishikawa K / Fujiyoshi Y
Funding support Japan, 2 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)20H00451 Japan
Japan Society for the Promotion of Science (JSPS)20K17245 Japan
CitationJournal: J Struct Biol / Year: 2025
Title: Structural insights into human adenylyl cyclase 9 in complex with Gαs by cryo-EM.
Authors: Risa Nomura / Shota Suzuki / Koki Nishikawa / Hiroshi Suzuki / Yoshinori Fujiyoshi /
Abstract: Adenylyl cyclase 9 (AC9) regulates many physiologic functions through the production of cAMP, an important second messenger that regulates downstream effectors. The activation of AC9 is highly ...Adenylyl cyclase 9 (AC9) regulates many physiologic functions through the production of cAMP, an important second messenger that regulates downstream effectors. The activation of AC9 is highly regulated by GPCR signaling. For example, AC9 is activated by the binding of Gαs, which, in turn, is activated by Gs-driven GPCRs. The structure of bovine AC9 (bAC9) was reported in 2019 using single-particle cryo-electron microscopy (cryo-EM). The structure of human AC9 (hAC9), however, has not been reported to date despite its potential benefit for drug development. Here, we analyzed the structures of hAC9 and hAC9 in complex with Gαs (hAC9-Gαs) using single-particle cryo-EM. The soluble domain of AC9-Gαs, the transmembrane (TM) domain of AC9-Gαs, and AC9 alone were analyzed at resolutions of 2.7 Å, 3.4 Å, and 3.2 Å, respectively. The results revealed three key aspects of the activation mechanism of hAC9 and its cAMP-generating function. First, a conformational change of the soluble domain was observed upon Gαs binding, resulting in a widely open catalytic site. Second, we analyzed the exact position of the C-terminus occluding the catalytic site in the hAC9-Gαs complex. Finally, we unexpectedly identified an elongated density suggestive of a single acyl chain in the TM domain. Consistent with recent reports on the allosteric regulation of AC by lipids, this finding suggests that the TM domain could serve as a potential drug target.These structural findings enhance our understanding of the structure and function of AC9 and other ACs and will provide a foundation for future AC-target drug discovery.
History
DepositionMar 18, 2025-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateDec 24, 2025-
Current statusDec 24, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_63823.png

Downloads & links

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Map

FileDownload / File: emd_63823.map.gz / Format: CCP4 / Size: 95 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain map
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.79 Å/pix.
x 292 pix.
= 230.68 Å		0.79 Å/pix.
x 292 pix.
= 230.68 Å		0.79 Å/pix.
x 292 pix.
= 230.68 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.79 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.242
Minimum - Maximum-1.1853836 - 2.2120495
Average (Standard dev.)0.0018249566 (±0.053056195)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions292292292
Spacing292292292
CellA=B=C: 230.68001 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_63823_msk_1.map
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Half map: half B

Fileemd_63823_half_map_1.map
Annotationhalf B
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Half map: half A

Fileemd_63823_half_map_2.map
Annotationhalf A
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Sample components

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Entire : human AC9 in complex with GalphaS

EntireName: human AC9 in complex with GalphaS
Components
  • Complex: human AC9 in complex with GalphaS
    • Protein or peptide: Adenylate cyclase type 9,Protein M2-1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
  • Ligand: 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: human AC9 in complex with GalphaS

SupramoleculeName: human AC9 in complex with GalphaS / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 150 kDa/nm

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Macromolecule #1: Adenylate cyclase type 9,Protein M2-1

MacromoleculeName: Adenylate cyclase type 9,Protein M2-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: adenylate cyclase
Source (natural)Organism: Human respiratory syncytial virus
Molecular weightTheoretical: 181.560188 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASPPHQQLL HHHSTEVSCD SSGDSNSVRV KINPKQLSSN SHPKHCKYSI SSSCSSSGDS GGVPRRVGGG GRLRRQKKLP QLFERASSR WWDPKFDSVN LEEACLERCF PQTQRRFRYA LFYIGFACLL WSIYFAVHMR SRLIVMVAPA LCFLLVCVGF F LFTFTKLY ...String:
MASPPHQQLL HHHSTEVSCD SSGDSNSVRV KINPKQLSSN SHPKHCKYSI SSSCSSSGDS GGVPRRVGGG GRLRRQKKLP QLFERASSR WWDPKFDSVN LEEACLERCF PQTQRRFRYA LFYIGFACLL WSIYFAVHMR SRLIVMVAPA LCFLLVCVGF F LFTFTKLY ARHYAWTSLA LTLLVFALTL AAQFQVLTPV SGRGDSSNLT ATARPTDTCL SQVGSFSMCI EVLFLLYTVM HL PLYLSLC LGVAYSVLFE TFGYHFRDEA CFPSPGAGAL HWELLSRGLL HGCIHAIGVH LFVMSQVRSR STFLKVGQSI MHG KDLEVE KALKERMIHS VMPRIIADDL MKQGDEESEN SVKRHATSSP KNRKKKSSIQ KAPIAFRPFK MQQIEEVSIL FADI VGFTK MSANKSAHAL VGLLNDLFGR FDRLCEETKC EKISTLGDCY YCVAGCPEPR ADHAYCCIEM GLGMIKAIEQ FCQEK KEMV NMRVGVHTGT VLCGILGMRR FKFDVWSNDV NLANLMEQLG VAGKVHISEA TAKYLDDRYE MEDGKVIERL GQSVVA DQL KGLKTYLISG QRAKESRCSC AEALLSGFEV IDGSQVSSGP RGQGTASSGN VSDLAQTVKT FDNLKTCPSC GITFAPK SE AGAEGGAPQN GCQDEHKNST KASGGPNPKT QNGLLSPPQE EKLTNSQTSL CEILQEKGRW AGVSLDQSAL LPLRFKNI R EKTDAHFVDV IKEDSLMKDY FFKPPINQFS LNFLDQELER SYRTSYQEEV IKNSPVKTFA SPTFSSLLDV FLSTTVFLT LSTTCFLKYE AATVPPPPAA LAVFSAALLL EVLSLAVSIR MVFFLEDVMA CTKRLLEWIA GWLPRHCIGA ILVSLPALAV YSHVTSEYE TNIHFPVFTG SAALIAVVHY CNFCQLSSWM RSSLATVVGA GPLLLLYVSL CPDSSVLTSP LDAVQNFSSE R NPCNSSVP RDLRRPASLI GQEVVLVFFL LLLLVWFLNR EFEVSYRLHY HGDVEADLHR TKIQSMRDQA DWLLRNIIPY HV AEQLKVS QTYSKNHDSG GVIFASIVNF SEFYEENYEG GKECYRVLNE LIGDFDELLS KPDYSSIEKI KTIGATYMAA SGL NTAQAQ DGSHPQEHLQ ILFEFAKEMM RVVDDFNNNM LWFNFKLRVG FNHGPLTAGV IGTTKLLYDI WGDTVNIASR MDTT GVECR IQVSEESYRV LSKMGYDFDY RGTVNVKGKG QMKTYLYPKC TDHRVIPQHQ LSISPDIRVQ VDGSIGRSPT DEIAN LVPS VQYVDKTSLG SDSSTQAKDA HLSPKRPWKE PVKAEERGRF GKAIEKDDCD ETGIEEANEL TKLNVSKSVG SNSENL YFQ GSMVSKGEEL FTGVVPILVE LDGDVNGHKF SVSGEGEGDA TYGKLTLKFI CTTGKLPVPW PTLVTTLTYG VQCFSRY PD HMKQHDFFKS AMPEGYVQER TIFFKDDGNY KTRAEVKFEG DTLVNRIELK GIDFKEDGNI LGHKLEYNYN SHNVYIMA D KQKNGIKVNF KIRHNIEDGS VQLADHYQQN TPIGDGPVLL PDNHYLSTQS KLSKDPNEKR DHMVLLEFVT AAGITLGMD ELYKHHHHHH HHHHDYKDDD DK

UniProtKB: Adenylate cyclase type 9, Protein M2-1

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Macromolecule #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.331168 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String:
MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGGQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ EALNLFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELLSN SENL YFQGS HHHHHHHHHH DYKDDDDK

UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

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Macromolecule #3: 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE

MacromoleculeName: 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE / type: ligand / ID: 3 / Number of copies: 1 / Formula: GSP
Molecular weightTheoretical: 539.246 Da
Chemical component information

ChemComp-GSP:
5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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

MicroscopeJEOL CRYO ARM 300
Image recordingFilm or detector model: GATAN K3 (6k 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: 1.5 µm / Nominal defocus min: 0.8 µm

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 170990
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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