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- EMDB-32342: Cryo-EM structure of the alpha2A adrenergic receptor GoA signalin... -

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Entry
Database: EMDB / ID: EMD-32342
TitleCryo-EM structure of the alpha2A adrenergic receptor GoA signaling complex bound to a biased agonist
Map dataCryo-EM structure of a biased agonist-bound signaling complex of alpha2A adrenergic receptor with GoA
Sample
  • Complex: Signaling complex of alpha2A adrenergic receptor with GoA
    • Protein or peptide: Guanine nucleotide-binding protein G(o) 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: scFv
    • Protein or peptide: Alpha-2A adrenergic receptor
  • Ligand: 5-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-1,2,3,6-tetrahydropyridine
KeywordsGPCR / G-protein / signaling complex / biased agonist / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of uterine smooth muscle contraction / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / alpha-2C adrenergic receptor binding / phospholipase C-activating adrenergic receptor signaling pathway / : / negative regulation of epinephrine secretion / epinephrine binding / negative regulation of norepinephrine secretion ...negative regulation of uterine smooth muscle contraction / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / alpha-2C adrenergic receptor binding / phospholipase C-activating adrenergic receptor signaling pathway / : / negative regulation of epinephrine secretion / epinephrine binding / negative regulation of norepinephrine secretion / alpha-1B adrenergic receptor binding / negative regulation of calcium ion transmembrane transporter activity / heterotrimeric G-protein binding / negative regulation of calcium ion-dependent exocytosis / activation of protein kinase activity / dopaminergic synapse / mu-type opioid receptor binding / Surfactant metabolism / corticotropin-releasing hormone receptor 1 binding / thermoception / positive regulation of potassium ion transport / fear response / thioesterase binding / negative regulation of insulin secretion involved in cellular response to glucose stimulus / vesicle docking involved in exocytosis / response to alcohol / positive regulation of membrane protein ectodomain proteolysis / norepinephrine binding / intestinal absorption / Adrenoceptors / positive regulation of epidermal growth factor receptor signaling pathway / response to morphine / G protein-coupled dopamine receptor signaling pathway / positive regulation of wound healing / adrenergic receptor signaling pathway / regulation of heart contraction / parallel fiber to Purkinje cell synapse / negative regulation of calcium ion transport / Rho protein signal transduction / regulation of vasoconstriction / postsynaptic modulation of chemical synaptic transmission / negative regulation of lipid catabolic process / negative regulation of insulin secretion / cellular response to hormone stimulus / activation of protein kinase B activity / adenylate cyclase-activating adrenergic receptor signaling pathway / presynaptic active zone membrane / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / muscle contraction / axon terminus / presynaptic modulation of chemical synaptic transmission / positive regulation of MAP kinase activity / guanyl-nucleotide exchange factor activity / positive regulation of cytokine production / GABA-ergic synapse / female pregnancy / locomotory behavior / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / postsynaptic density membrane / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / platelet activation / G-protein beta/gamma-subunit complex binding / 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-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / 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 / cellular response to catecholamine stimulus / vasodilation / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / glucose homeostasis / heterotrimeric G-protein complex
Similarity search - Function
Alpha 2A adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / G-protein, gamma subunit ...Alpha 2A adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / 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 / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Alpha-2A adrenergic receptor / Guanine nucleotide-binding protein G(o) subunit alpha / 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) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsXu J / Fink EA
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Science / Year: 2022
Title: Structure-based discovery of nonopioid analgesics acting through the α-adrenergic receptor.
Authors: Elissa A Fink / Jun Xu / Harald Hübner / Joao M Braz / Philipp Seemann / Charlotte Avet / Veronica Craik / Dorothee Weikert / Maximilian F Schmidt / Chase M Webb / Nataliya A Tolmachova / ...Authors: Elissa A Fink / Jun Xu / Harald Hübner / Joao M Braz / Philipp Seemann / Charlotte Avet / Veronica Craik / Dorothee Weikert / Maximilian F Schmidt / Chase M Webb / Nataliya A Tolmachova / Yurii S Moroz / Xi-Ping Huang / Chakrapani Kalyanaraman / Stefan Gahbauer / Geng Chen / Zheng Liu / Matthew P Jacobson / John J Irwin / Michel Bouvier / Yang Du / Brian K Shoichet / Allan I Basbaum / Peter Gmeiner /
Abstract: Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new ...Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new αAR agonists chemotypes that lack the sedation conferred by known αAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G and G signaling. Experimental structures of αAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC) of 52 nanomolar] and two analogs, '7075 and PS75 (EC 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.
History
DepositionDec 4, 2021-
Header (metadata) releaseSep 28, 2022-
Map releaseSep 28, 2022-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32342.png

Downloads & links

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Map

FileDownload / File: emd_32342.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of a biased agonist-bound signaling complex of alpha2A adrenergic receptor with GoA
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å		0.85 Å/pix.
x 320 pix.
= 272. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-2.067788 - 3.3453677
Average (Standard dev.)-0.0010246352 (±0.073538475)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Signaling complex of alpha2A adrenergic receptor with GoA

EntireName: Signaling complex of alpha2A adrenergic receptor with GoA
Components
  • Complex: Signaling complex of alpha2A adrenergic receptor with GoA
    • Protein or peptide: Guanine nucleotide-binding protein G(o) 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: scFv
    • Protein or peptide: Alpha-2A adrenergic receptor
  • Ligand: 5-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-1,2,3,6-tetrahydropyridine

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Supramolecule #1: Signaling complex of alpha2A adrenergic receptor with GoA

SupramoleculeName: Signaling complex of alpha2A adrenergic receptor with GoA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(o) subunit alpha

MacromoleculeName: Guanine nucleotide-binding protein G(o) subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.1005 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG AGESGKSTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY ...String:
MGCTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG AGESGKSTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY QPTEQDILRT RVKTTGIVET HFTFKNLHFR LFDVGGQRSE RKKWIHCFED VTAIIFCVAL SGYDQVLHED ET TNRMHES LMLFDSICNN KFFIDTSIIL FLNKKDLFGE KIKKSPLTIC FPEYTGPNTY EDAAAYIQAQ FESKNRSPNK EIY CHMTCA TDTNNIQVVF DAVTDIIIAN NLRGCGLY

UniProtKB: Guanine nucleotide-binding protein G(o) subunit alpha

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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: 38.402867 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: HHHHHHGSSG SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT ...String:
HHHHHHGSSG SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT SSGDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NA ICFFPNG NAFATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGH DNRVSC LGVTDDGMAV ATGSWDSFLK IWN

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: Trichoplusia ni (cabbage looper)
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: scFv

MacromoleculeName: scFv / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 32.898781 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFADV QLVESGGGLV QPGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSEDT AMYYCVRSIY YYGSSPFDFW GQGTTLTVSS G GGGSGGGG ...String:
MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFADV QLVESGGGLV QPGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSEDT AMYYCVRSIY YYGSSPFDFW GQGTTLTVSS G GGGSGGGG SGGGGSDIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLELKG SLEVLFQGPA AAHHHHHHHH

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Macromolecule #5: Alpha-2A adrenergic receptor

MacromoleculeName: Alpha-2A adrenergic receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.704566 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MFRQEQPLAE GSFAPMGSLQ PDAGNASWNG TEAPGGGARA TPYSLQVTLT LVCLAGLLML LTVFGNVLVI IAVFTSRALK APQNLFLVS LASADILVAT LVIPFSLANE VMGYWYFGKA WCEIYLALDV LFCTSSIVHL CAISLDRYWS ITQAIEYNLK R TPRRIKAI ...String:
MFRQEQPLAE GSFAPMGSLQ PDAGNASWNG TEAPGGGARA TPYSLQVTLT LVCLAGLLML LTVFGNVLVI IAVFTSRALK APQNLFLVS LASADILVAT LVIPFSLANE VMGYWYFGKA WCEIYLALDV LFCTSSIVHL CAISLDRYWS ITQAIEYNLK R TPRRIKAI IITVWVISAV ISFPPLISIE KKGGGGGPQP AEPRCEINDQ KWYVISSCIG SFFAPCLIMI LVYVRIYQIA KR RTRVPPS RRGPDAVAAP PGGTERRPNG LGPERSAGPG GAEAEPLPTQ LNGAPGEPAP AGPRDTDALD LEESSSSDHA ERP PGPRRP ERGPRGKGKA RASQVKPGDS LPRRGPGATG IGTPAAGPGE ERVGAAKASR WRGRQNREKR FTFVLAVVIG VFVV CWFPF FFTYTLTAVG CSVPRTLFKF FFWFGYCNSS LNPVIYTIFN HDFRRAFKKI LCRGDRKRIV

UniProtKB: Alpha-2A adrenergic receptor

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Macromolecule #6: 5-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-1,2,3,6-tetrahydropyridine

MacromoleculeName: 5-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-1,2,3,6-tetrahydropyridine
type: ligand / ID: 6 / Number of copies: 1 / Formula: W58
Molecular weightTheoretical: 185.265 Da
Chemical component information

ChemComp-W58:
5-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-1,2,3,6-tetrahydropyridine

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6k41

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 563506
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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