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- PDB-9u3p: Cryo-EM structure of human AC9-Gs complex (soluble domain) -

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Basic information

Entry
Database: PDB / ID: 9u3p
TitleCryo-EM structure of human AC9-Gs complex (soluble domain)
Components
  • Adenylate cyclase type 9,Protein M2-1
  • Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
KeywordsMEMBRANE PROTEIN / enzyme
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
5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE / 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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.65 Å
AuthorsSuzuki, S. / Nomura, R. / Suzuki, H. / Nishikawa, K. / Fujiyoshi, Y.
Funding support Japan, 2items
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, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Adenylate cyclase type 9,Protein M2-1
B: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
hetero molecules


Theoretical massNumber of molelcules
Total (without water)231,4554
Polymers230,8912
Non-polymers5642
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Adenylate cyclase type 9,Protein M2-1 / ATP pyrophosphate-lyase 9 / Adenylate cyclase type IX / ACIX / Adenylyl cyclase 9 / AC9 / Envelope- ...ATP pyrophosphate-lyase 9 / Adenylate cyclase type IX / ACIX / Adenylyl cyclase 9 / AC9 / Envelope-associated 22 kDa protein / Transcription antitermination factor M2-1


Mass: 181560.188 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Human respiratory syncytial virus
Gene: ADCY9, KIAA0520, M2-1mGFP / Production host: Homo sapiens (human)
References: UniProt: O60503, UniProt: A0A1S5SHT2, adenylate cyclase
#2: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 49331.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P63092, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#3: Chemical ChemComp-GSP / 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE


Mass: 539.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human AC9 in complex with GalphaS / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 150 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 170990 / Symmetry type: POINT
RefinementHighest resolution: 2.65 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0026787
ELECTRON MICROSCOPYf_angle_d0.449167
ELECTRON MICROSCOPYf_dihedral_angle_d4.678917
ELECTRON MICROSCOPYf_chiral_restr0.041003
ELECTRON MICROSCOPYf_plane_restr0.0031186

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