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- EMDB-35135: FSHR-Follicle stimulating hormone-compound 716340-Gs complex -

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Basic information

Entry
Database: EMDB / ID: EMD-35135
TitleFSHR-Follicle stimulating hormone-compound 716340-Gs complex
Map dataDeepEMhancer sharpen
Sample
  • Complex: FSHR-Follicle stimulating hormone-compound 716340-Gs complex
    • Protein or peptide: x 7 types
  • Ligand: x 5 types
Function / homology
Function and homology information


follicle-stimulating hormone receptor activity / progesterone biosynthetic process / follicle-stimulating hormone activity / follicle-stimulating hormone complex / pituitary gonadotropin complex / luteinizing hormone secretion / follicle-stimulating hormone secretion / positive regulation of steroid biosynthetic process / Thyroxine biosynthesis / Mineralocorticoid biosynthesis ...follicle-stimulating hormone receptor activity / progesterone biosynthetic process / follicle-stimulating hormone activity / follicle-stimulating hormone complex / pituitary gonadotropin complex / luteinizing hormone secretion / follicle-stimulating hormone secretion / positive regulation of steroid biosynthetic process / Thyroxine biosynthesis / Mineralocorticoid biosynthesis / Hormone ligand-binding receptors / Glycoprotein hormones / Reactions specific to the complex N-glycan synthesis pathway / Androgen biosynthesis / follicle-stimulating hormone signaling pathway / female gamete generation / Sertoli cell proliferation / gonad development / negative regulation of organ growth / cellular response to follicle-stimulating hormone stimulus / regulation of osteoclast differentiation / sensory perception of chemical stimulus / mu-type opioid receptor binding / regulation of protein kinase A signaling / corticotropin-releasing hormone receptor 1 binding / thyroid hormone generation / G protein-coupled peptide receptor activity / regulation of signaling receptor activity / beta-2 adrenergic receptor binding / organ growth / female gonad development / PKA activation in glucagon signalling / thyroid gland development / developmental growth / D1 dopamine receptor binding / positive regulation of bone resorption / positive regulation of cAMP-mediated signaling / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / adenylate cyclase activator activity / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / hormone-mediated signaling pathway / transforming growth factor beta receptor signaling pathway / female pregnancy / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / bone development / 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 / 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 / hormone activity / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / platelet aggregation / Adrenaline,noradrenaline inhibits insulin secretion / positive regulation of GTPase activity / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Golgi lumen / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / male gonad development / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events
Similarity search - Function
Follicle stimulating hormone receptor / Gonadotropin hormone receptor, transmembrane domain / Gonadotropin hormone receptor transmembrane region / Gonadotropin, beta subunit, conserved site / Glycoprotein hormones beta chain signature 1. / Glycoprotein hormones beta chain signature 2. / Glycoprotein hormone beta chain homologues. / Glycoprotein hormone alpha chain / Glycoprotein hormone / Glycoprotein hormones alpha chain signature 1. ...Follicle stimulating hormone receptor / Gonadotropin hormone receptor, transmembrane domain / Gonadotropin hormone receptor transmembrane region / Gonadotropin, beta subunit, conserved site / Glycoprotein hormones beta chain signature 1. / Glycoprotein hormones beta chain signature 2. / Glycoprotein hormone beta chain homologues. / Glycoprotein hormone alpha chain / Glycoprotein hormone / Glycoprotein hormones alpha chain signature 1. / Glycoprotein hormones alpha chain signature 2. / Glycoprotein hormones alpha chain family profile. / Glycoprotein hormone alpha chain homologues. / Gonadotropin, beta subunit / Glycoprotein hormone subunit beta / Cystine-knot domain / Glycoprotein hormone receptor family / BspA type Leucine rich repeat region / BspA type Leucine rich repeat region (6 copies) / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Cystine-knot cytokine / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / Leucine-rich repeat domain superfamily / 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 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / 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
Glycoprotein hormones alpha chain / Follitropin subunit beta / Follicle-stimulating hormone receptor / 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 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / Guanine nucleotide-binding protein G(s) subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsDuan J / Xu P / Yang J / Ji Y / Zhang H / Mao C / Luan X / Jiang Y / Zhang Y / Zhang S / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
CitationJournal: Nat Commun / Year: 2023
Title: Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor.
Authors: Jia Duan / Peiyu Xu / Huibing Zhang / Xiaodong Luan / Jiaqi Yang / Xinheng He / Chunyou Mao / Dan-Dan Shen / Yujie Ji / Xi Cheng / Hualiang Jiang / Yi Jiang / Shuyang Zhang / Yan Zhang / H Eric Xu /
Abstract: Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes ...Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes infertility and ovarian hyperstimulation syndrome. Here we report cryo-EM structures of FSHR in both inactive and active states, with the active structure bound to FSH and an allosteric agonist compound 21 f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21 f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H615 in FSHR plays an essential role in determining FSHR selectivity for various allosteric agonists. Together, our structures provide a molecular basis of FSH and small allosteric agonist-mediated FSHR activation, which could inspire the design of FSHR-targeted drugs for the treatment of infertility and controlled ovarian stimulation for in vitro fertilization.
History
DepositionJan 14, 2023-
Header (metadata) releaseMar 29, 2023-
Map releaseMar 29, 2023-
UpdateApr 5, 2023-
Current statusApr 5, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_35135.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDeepEMhancer sharpen
Voxel sizeX=Y=Z: 1.03 Å
Density
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.01809171 - 1.814094
Average (Standard dev.)0.0014242994 (±0.02514007)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 263.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Locel map on FSH and FSHR-ECD

Fileemd_35135_additional_1.map
AnnotationLocel map on FSH and FSHR-ECD
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Additional map: b-factor sharpen

Fileemd_35135_additional_2.map
Annotationb-factor sharpen
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #1

Fileemd_35135_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #2

Fileemd_35135_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Sample components

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Entire : FSHR-Follicle stimulating hormone-compound 716340-Gs complex

EntireName: FSHR-Follicle stimulating hormone-compound 716340-Gs complex
Components
  • Complex: FSHR-Follicle stimulating hormone-compound 716340-Gs complex
    • Protein or peptide: chimera of Guanine nucleotide-binding protein G(s) subunit alpha and Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
    • 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: Nb35
    • Protein or peptide: Follicle-stimulating hormone receptor
    • Protein or peptide: Glycoprotein hormones alpha chain
    • Protein or peptide: Follitropin subunit beta
  • Ligand: CHOLESTEROL
  • Ligand: PALMITIC ACID
  • Ligand: MYRISTIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: N-tert-butyl-N-ethyl-8-methoxy-9-propan-2-yloxy-1-thiophen-2-yl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide

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Supramolecule #1: FSHR-Follicle stimulating hormone-compound 716340-Gs complex

SupramoleculeName: FSHR-Follicle stimulating hormone-compound 716340-Gs complex
type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#7
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: chimera of Guanine nucleotide-binding protein G(s) subunit alpha ...

MacromoleculeName: chimera of Guanine nucleotide-binding protein G(s) subunit alpha and Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.168227 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MNSKTEDQRN EEKAQREANK KIEKQLQKDK QVYRATHRLL LLGAGESGKS TIVKQMRILH GGSGGSGGTT GIFETKFQVD KVNFHMFDV GGQRDERRKW IQCFNDVTAI IFVVASSSYN MVIREDNQTN RLQEALNLFK SIWNNRWLRT ISVILFLNKQ D LLAEKVLA ...String:
MNSKTEDQRN EEKAQREANK KIEKQLQKDK QVYRATHRLL LLGAGESGKS TIVKQMRILH GGSGGSGGTT GIFETKFQVD KVNFHMFDV GGQRDERRKW IQCFNDVTAI IFVVASSSYN MVIREDNQTN RLQEALNLFK SIWNNRWLRT ISVILFLNKQ D LLAEKVLA GKSKIEDYFP EFARYTTPED ATPEPGEDPR VTRAKYFIRD EFLRISTASG DGRHYCYPHF TCAVDTENIR RV FNDCRDI IQRMHLRQYE LL

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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: 37.915496 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String:
MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN

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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

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Macromolecule #4: Nb35

MacromoleculeName: Nb35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 13.885439 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS

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Macromolecule #5: Follicle-stimulating hormone receptor

MacromoleculeName: Follicle-stimulating hormone receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 76.68368 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: CHHRICHCSN RVFLCQESKV TEIPSDLPRN AIELRFVLTK LRVIQKGAFS GFGDLEKIEI SQNDVLEVIE ADVFSNLPKL HEIRIEKAN NLLYINPEAF QNLPNLQYLL ISNTGIKHLP DVHKIHSLQK VLLDIQDNIN IHTIERNSFV GLSFESVILW L NKNGIQEI ...String:
CHHRICHCSN RVFLCQESKV TEIPSDLPRN AIELRFVLTK LRVIQKGAFS GFGDLEKIEI SQNDVLEVIE ADVFSNLPKL HEIRIEKAN NLLYINPEAF QNLPNLQYLL ISNTGIKHLP DVHKIHSLQK VLLDIQDNIN IHTIERNSFV GLSFESVILW L NKNGIQEI HNCAFNGTQL DELNLSDNNN LEELPNDVFH GASGPVILDI SRTRIHSLPS YGLENLKKLR ARSTYNLKKL PT LEKLVAL MEASLTYPIH CCAFANWRRQ ISELHPICNK SILRQEVDYM TQARGQRSSL AEDNESSYSR GFDMTYTEFD YDL CNEVVD VTCSPKPDAF NPCEDIMGYN ILRVLIWFIS ILAITGNIIV LVILTTSQYK LTVPRFLMCN LAFADLCIGI YLLL IASVD IHTKSQYHNY AIDWQTGAGC DAAGFFTVFA SELSVYTLTA ITLERWHTIT HAMQLDCKVQ LRHAASVMVM GWIFA FAAA LFPIFGISSY MKVSICLPMD IDSPLSQLYV MSLLVLNVLA FVVICGCYIH IYLTVRNPNI VSSSSDTRIA KRMAML IFT DFLCMAPISF FAISASLKVP LITVSKAKIL LVLFHPINSC ANPFLYAIFT KNFRRDFFIL LSKCGCYEMQ AQIYRTE TS STVHNTHPRN GHCSSAPRVT NGSTYILVPL SHLAQN

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Macromolecule #6: Glycoprotein hormones alpha chain

MacromoleculeName: Glycoprotein hormones alpha chain / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.183753 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
APDVQDCPEC TLQENPLFSQ PGAPILQCMG CCFSRAYPTP LRSKKTMLVQ KNVTSESTCC VAKSYNRVTV MGGFKVENHT ACHCSTCYY HKS

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Macromolecule #7: Follitropin subunit beta

MacromoleculeName: Follitropin subunit beta / type: protein_or_peptide / ID: 7 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.241914 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
NSCELTNITI AIEKEECRFC ISINTTWCAG YCYTRDLVYK DPARPKIQKT CTFKELVYET VRVPGCAHHA DSLYTYPVAT QCHCGKCDS DSTDCTVRGL GPSYCSFGEM

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Macromolecule #9: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 9 / Number of copies: 13 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #10: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 10 / Number of copies: 3 / Formula: PLM
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

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Macromolecule #11: MYRISTIC ACID

MacromoleculeName: MYRISTIC ACID / type: ligand / ID: 11 / Number of copies: 2 / Formula: MYR
Molecular weightTheoretical: 228.371 Da
Chemical component information

ChemComp-MYR:
MYRISTIC ACID / Myristic acid

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Macromolecule #12: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 12 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #13: N-tert-butyl-N-ethyl-8-methoxy-9-propan-2-yloxy-1-thiophen-2-yl-5...

MacromoleculeName: N-tert-butyl-N-ethyl-8-methoxy-9-propan-2-yloxy-1-thiophen-2-yl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide
type: ligand / ID: 13 / Number of copies: 1 / Formula: O6F
Molecular weightTheoretical: 467.624 Da
Chemical component information

ChemComp-O6F:
N-tert-butyl-N-ethyl-8-methoxy-9-propan-2-yloxy-1-thiophen-2-yl-5,6-dihydroimidazo[5,1-a]isoquinoline-3-carboxamide

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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-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 477950

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