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- EMDB-43712: Human EBP complexed with compound 1 -

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Basic information

Entry
Database: EMDB / ID: EMD-43712
TitleHuman EBP complexed with compound 1
Map data
Sample
  • Complex: EBP complexed with compound 1
    • Protein or peptide: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
  • Ligand: 1-methyl-1'-[(oxan-4-yl)methyl]-5-(trifluoromethyl)spiro[indole-2,4'-piperidin]-3(1H)-one
KeywordsEmopamil-Binding Protein Isomerization Protein structure complex / STRUCTURAL PROTEIN / ISOMERASE-INHIBITOR complex
Function / homology
Function and homology information


cholestenol Delta-isomerase / C-8 sterol isomerase activity / cholesterol biosynthetic process via desmosterol / cholesterol biosynthetic process via lathosterol / cholestenol delta-isomerase activity / Cholesterol biosynthesis via desmosterol / Cholesterol biosynthesis via lathosterol / sterol biosynthetic process / steroid delta-isomerase activity / ossification involved in bone maturation ...cholestenol Delta-isomerase / C-8 sterol isomerase activity / cholesterol biosynthetic process via desmosterol / cholesterol biosynthetic process via lathosterol / cholestenol delta-isomerase activity / Cholesterol biosynthesis via desmosterol / Cholesterol biosynthesis via lathosterol / sterol biosynthetic process / steroid delta-isomerase activity / ossification involved in bone maturation / cholesterol biosynthetic process / hemopoiesis / cholesterol metabolic process / nuclear envelope / cytoplasmic vesicle / endoplasmic reticulum membrane / endoplasmic reticulum / identical protein binding
Similarity search - Function
Emopamil-binding protein / EXPERA domain / EXPERA domain profile.
Similarity search - Domain/homology
3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsSun D / Masureel M
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2024
Title: Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation.
Authors: Ruth Dorel / Dawei Sun / Nicholas Carruthers / Georgette M Castanedo / Peter M-U Ung / Daniel C Factor / Tianbo Li / Hannah Baumann / Danielle Janota / Jodie Pang / Laurent Salphati / Robert ...Authors: Ruth Dorel / Dawei Sun / Nicholas Carruthers / Georgette M Castanedo / Peter M-U Ung / Daniel C Factor / Tianbo Li / Hannah Baumann / Danielle Janota / Jodie Pang / Laurent Salphati / Robert Meklemburg / Allison J Korman / Halie E Harper / Samantha Stubblefield / Jian Payandeh / Daniel McHugh / Bradley T Lang / Paul J Tesar / Edward Dere / Matthieu Masureel / Drew J Adams / Matthew Volgraf / Marie-Gabrielle Braun /
Abstract: The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential ...The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor demonstrated strong target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis.
History
DepositionFeb 14, 2024-
Header (metadata) releaseJun 19, 2024-
Map releaseJun 19, 2024-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43712.png

Downloads & links

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Map

FileDownload / File: emd_43712.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.2 Å/pix.
x 192 pix.
= 230.4 Å		1.2 Å/pix.
x 192 pix.
= 230.4 Å		1.2 Å/pix.
x 192 pix.
= 230.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.2 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.53
Minimum - Maximum-6.5362716 - 10.272906000000001
Average (Standard dev.)0.009034913 (±0.25730962)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 230.40001 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: unsharpened map

Fileemd_43712_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_43712_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_43712_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : EBP complexed with compound 1

EntireName: EBP complexed with compound 1
Components
  • Complex: EBP complexed with compound 1
    • Protein or peptide: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
  • Ligand: 1-methyl-1'-[(oxan-4-yl)methyl]-5-(trifluoromethyl)spiro[indole-2,4'-piperidin]-3(1H)-one

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Supramolecule #1: EBP complexed with compound 1

SupramoleculeName: EBP complexed with compound 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase

MacromoleculeName: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: cholestenol Delta-isomerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.421871 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MWSHPQFEKT TNAGPLHPYW PQHLRLDNFV PNDRPTWHIL AGLFSVTGVL VVTTWLLSGR AAVVPLGTWR RLSLCWFAVC GFIHLVIEG WFVLYYEDLL GDQAFLSQLW KEYAKGDSRY ILGDNFTVCM ETITACLWGP LSLWVVIAFL RQHPLRFILQ L VVSVGQIY ...String:
MWSHPQFEKT TNAGPLHPYW PQHLRLDNFV PNDRPTWHIL AGLFSVTGVL VVTTWLLSGR AAVVPLGTWR RLSLCWFAVC GFIHLVIEG WFVLYYEDLL GDQAFLSQLW KEYAKGDSRY ILGDNFTVCM ETITACLWGP LSLWVVIAFL RQHPLRFILQ L VVSVGQIY GDVLYFLTEH RDGFQHGELG HPLYFWFYFV FMNALWLVLP GVLVLDAVKH LTHAQSTLDA KATKAKSKKN

UniProtKB: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase

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Macromolecule #2: 1-methyl-1'-[(oxan-4-yl)methyl]-5-(trifluoromethyl)spiro[indole-2...

MacromoleculeName: 1-methyl-1'-[(oxan-4-yl)methyl]-5-(trifluoromethyl)spiro[indole-2,4'-piperidin]-3(1H)-one
type: ligand / ID: 2 / Number of copies: 2 / Formula: A1AEU
Molecular weightTheoretical: 382.42 Da

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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 / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.009 e/Å2
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:

6ohu

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 146883
FSC plot (resolution estimation)

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