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- EMDB-40572: Human adenylyl Cyclase 5 in complex with Gbg -

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Basic information

Entry
Database: EMDB / ID: EMD-40572
TitleHuman adenylyl Cyclase 5 in complex with Gbg
Map data
Sample
  • Complex: Human adenylyl cyclase 5 in complex with Gbg
    • Protein or peptide: Adenylate cyclase type 5
    • 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
  • Ligand: GERAN-8-YL GERAN
KeywordsAdenylyl cyclase / G-proteins / complex / SIGNALING PROTEIN
Function / homology
Function and homology information


Adenylate cyclase activating pathway / adenylate cyclase-inhibiting dopamine receptor signaling pathway / G protein-coupled adenosine receptor signaling pathway / adenylate cyclase / regulation of insulin secretion involved in cellular response to glucose stimulus / cAMP biosynthetic process / adenylate cyclase activity / PKA activation / PKA activation in glucagon signalling / neuromuscular process controlling balance ...Adenylate cyclase activating pathway / adenylate cyclase-inhibiting dopamine receptor signaling pathway / G protein-coupled adenosine receptor signaling pathway / adenylate cyclase / regulation of insulin secretion involved in cellular response to glucose stimulus / cAMP biosynthetic process / adenylate cyclase activity / PKA activation / PKA activation in glucagon signalling / neuromuscular process controlling balance / adenylate cyclase binding / Adenylate cyclase inhibitory pathway / Hedgehog 'off' state / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / FCGR3A-mediated IL10 synthesis / locomotory 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 / cilium / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / 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 / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / 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 / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / scaffold protein binding / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / intracellular signal transduction / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / ATP binding / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Adenylate cyclase, conserved domain / Adenylate cyclase / Adenylate cyclase, N-terminal / Adenylate cyclase, conserved domain / Adenylyl cyclase N-terminal extracellular and transmembrane region / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Adenylate and Guanylate cyclase catalytic domain ...Adenylate cyclase, conserved domain / Adenylate cyclase / Adenylate cyclase, N-terminal / Adenylate cyclase, conserved domain / Adenylyl cyclase N-terminal extracellular and transmembrane region / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Adenylate and Guanylate cyclase catalytic domain / Guanylate cyclase domain profile. / Nucleotide cyclase / 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 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
Adenylate cyclase type 5 / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.0 Å
AuthorsYen YC / Tesmer JJG
Funding support United States, 5 items
OrganizationGrant numberCountry
American Heart Association903842 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA254402 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA221289 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA023168 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL071818 United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structure of adenylyl cyclase 5 in complex with Gβγ offers insights into ADCY5-related dyskinesia.
Authors: Yu-Chen Yen / Yong Li / Chun-Liang Chen / Thomas Klose / Val J Watts / Carmen W Dessauer / John J G Tesmer /
Abstract: The nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, Gα, but their response to Gβγ regulation is isoform specific. In ...The nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, Gα, but their response to Gβγ regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gβγ and a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. Gain-of-function mutations in AC5 associated with human familial dyskinesia are located at the interface of AC5 with Gβγ and show reduced conditional activation by Gβγ, emphasizing the importance of the observed interaction for motor function in humans. We propose a molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core. As our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development.
History
DepositionApr 20, 2023-
Header (metadata) releaseApr 3, 2024-
Map releaseApr 3, 2024-
UpdateApr 24, 2024-
Current statusApr 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40572.png

Downloads & links

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Map

FileDownload / File: emd_40572.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-1.9450669 - 3.5848818
Average (Standard dev.)0.0044464334 (±0.07509252)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 276.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_40572_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_40572_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human adenylyl cyclase 5 in complex with Gbg

EntireName: Human adenylyl cyclase 5 in complex with Gbg
Components
  • Complex: Human adenylyl cyclase 5 in complex with Gbg
    • Protein or peptide: Adenylate cyclase type 5
    • 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
  • Ligand: GERAN-8-YL GERAN

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Supramolecule #1: Human adenylyl cyclase 5 in complex with Gbg

SupramoleculeName: Human adenylyl cyclase 5 in complex with Gbg / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Macromolecule #1: Adenylate cyclase type 5

MacromoleculeName: Adenylate cyclase type 5 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: adenylate cyclase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 139.066312 KDa
Recombinant expressionOrganism: Mammalia (mammals)
SequenceString: MSGSKSVSPP GYAAQKTAAP APRGGPEHRS AWGEADSRAN GYPHAPGGSA RGSTKKPGGA VTPQQQQRLA SRWRSDDDDD PPLSGDDPL AGGFGFSFRS KSAWQERGGD DCGRGSRRQR RGAASGGSTR APPAGGGGGS AAAAASAGGT EVRPRSVEVG L EERRGKGR ...String:
MSGSKSVSPP GYAAQKTAAP APRGGPEHRS AWGEADSRAN GYPHAPGGSA RGSTKKPGGA VTPQQQQRLA SRWRSDDDDD PPLSGDDPL AGGFGFSFRS KSAWQERGGD DCGRGSRRQR RGAASGGSTR APPAGGGGGS AAAAASAGGT EVRPRSVEVG L EERRGKGR AADELEAGAV EGGEGSGDGG SSADSGSGAG PGAVLSLGAC CLALLQIFRS KKFPSDKLER LYQRYFFRLN QS SLTMLMA VLVLVCLVML AFHAARPPLQ LPYLAVLAAA VGVILIMAVL CNRAAFHQDH MGLACYALIA VVLAVQVVGL LLP QPRSAS EGIWWTVFFI YTIYTLLPVR MRAAVLSGVL LSALHLAIAL RTNAQDQFLL KQLVSNVLIF SCTNIVGVCT HYPA EVSQR QAFQETRECI QARLHSQREN QQQERLLLSV LPRHVAMEMK ADINAKQEDM MFHKIYIQKH DNVSILFADI EGFTS LASQ CTAQELVMTL NELFARFDKL AAENHCLRIK ILGDCYYCVS GLPEARADHA HCCVEMGMDM IEAISLVREV TGVNVN MRV GIHSGRVHCG VLGLRKWQFD VWSNDVTLAN HMEAGGKAGR IHITKATLNY LNGDYEVEPG CGGERNAYLK EHSIETF LI LRCTQKRKEE KAMIAKMNRQ RTNSIGHNPP HWGAERPFYN HLGGNQVSKE MKRMGFEDPK DKNAQESANP EDEVDEFL G RAIDARSIDR LRSEHVRKFL LTFREPDLEK KYSKQVDDRF GAYVACASLV FLFICFVQIT IVPHSIFMLS FYLTCSLLL TLVVFVSVIY SCVKLFPSPL QTLSRKIVRS KMNSTLVGVF TITLVFLAAF VNMFTCNSRD LLGCLAQEHN ISASQVNACH VAESAVNYS LGDEQGFCGS PWPNCNFPEY FTYSVLLSLL ACSVFLQISC IGKLVLMLAI ELIYVLIVEV PGVTLFDNAD L LVTANAID FFNNGTSQCP EHATKVALKV VTPIIISVFV LALYLHAQQV ESTARLDFLW KLQATEEKEE MEELQAYNRR LL HNILPKD VAAHFLARER RNDELYYQSC ECVAVMFASI ANFSEFYVEL EANNEGVECL RLLNEIIADF DEIISEDRFR QLE KIKTIG STYMAASGLN DSTYDKVGKT HIKALADFAM KLMDQMKYIN EHSFNNFQMK IGLNIGPVVA GVIGARKPQY DIWG NTVNV ASRMDSTGVP DRIQVTTDMY QVLAANTYQL ECRGVVKVKG KGEMMTYFLN GGPPLS

UniProtKB: Adenylate cyclase type 5

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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

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

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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: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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

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Macromolecule #4: GERAN-8-YL GERAN

MacromoleculeName: GERAN-8-YL GERAN / type: ligand / ID: 4 / Number of copies: 1 / Formula: GER
Molecular weightTheoretical: 274.484 Da
Chemical component information

ChemComp-GER:
GERAN-8-YL GERAN

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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

Concentration0.2 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
137.0 mMNaClSodium chlorideSodium Chloride
2.7 mMKClPotassium Chloride
8.0 mMNa2HPO4Sodium hydrogen phosphate
2.0 mMKH2PO4Potassium dihydrogen phosphate
0.01 %C47H88O22LMNG
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.8 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1251384
Startup modelType of model: NONE
Initial angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
Final angle assignmentType: COMMON LINE / Software - Name: cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 7.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 61870

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