+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-40573 | ||||||||||||||||||
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Title | Dimeric form of human adenylyl cyclase 5 | ||||||||||||||||||
Map data | |||||||||||||||||||
Sample |
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Keywords | Adenylyl cyclase / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / cilium / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / scaffold protein binding / intracellular signal transduction / ATP binding / membrane / metal ion binding / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 7.0 Å | ||||||||||||||||||
Authors | Yen YC / Tesmer JJG | ||||||||||||||||||
Funding support | United States, 5 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_40573.map.gz | 96.4 MB | EMDB map data format | |
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Header (meta data) | emd-40573-v30.xml emd-40573.xml | 17.8 KB 17.8 KB | Display Display | EMDB header |
Images | emd_40573.png | 123.9 KB | ||
Filedesc metadata | emd-40573.cif.gz | 6.3 KB | ||
Others | emd_40573_half_map_1.map.gz emd_40573_half_map_2.map.gz | 94.9 MB 94.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-40573 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-40573 | HTTPS FTP |
-Validation report
Summary document | emd_40573_validation.pdf.gz | 684.2 KB | Display | EMDB validaton report |
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Full document | emd_40573_full_validation.pdf.gz | 683.8 KB | Display | |
Data in XML | emd_40573_validation.xml.gz | 13.5 KB | Display | |
Data in CIF | emd_40573_validation.cif.gz | 15.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40573 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40573 | HTTPS FTP |
-Related structure data
Related structure data | 8sl4MC 8sl3C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_40573.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.08 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_40573_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_40573_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Dimeric form of human adenylyl cyclase 5
Entire | Name: Dimeric form of human adenylyl cyclase 5 |
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Components |
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-Supramolecule #1: Dimeric form of human adenylyl cyclase 5
Supramolecule | Name: Dimeric form of human adenylyl cyclase 5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 280 KDa |
-Macromolecule #1: Adenylate cyclase type 5
Macromolecule | Name: Adenylate cyclase type 5 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: adenylate cyclase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 139.066312 KDa |
Recombinant expression | Organism: Mammalia (mammals) |
Sequence | String: 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 |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.2 mg/mL | ||||||||||||||||||
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Buffer | pH: 7.4 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY | ||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.8 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 7.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 102581 |
Initial angle assignment | Type: COMMON LINE / Software - Name: cryoSPARC |
Final angle assignment | Type: COMMON LINE / Software - Name: cryoSPARC |