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- PDB-8w0r: Human EBP complexed with compound 1 -

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Basic information

Entry
Database: PDB / ID: 8w0r
TitleHuman EBP complexed with compound 1
Components3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
KeywordsISOMERASE/INHIBITOR / Emopamil-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 / steroid Delta-isomerase activity / ossification involved in bone maturation / cholesterol biosynthetic process ...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 / steroid Delta-isomerase activity / ossification involved in bone maturation / cholesterol biosynthetic process / hemopoiesis / cholesterol metabolic process / nuclear envelope / nuclear membrane / cytoplasmic vesicle / endoplasmic reticulum membrane / endoplasmic reticulum / identical protein binding
Similarity search - Function
Emopamil-binding protein / EXPERA domain / EXPERA (EXPanded EBP superfamily) / EXPERA domain profile.
Similarity search - Domain/homology
: / 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsSun, D. / Masureel, M.
Funding support1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
B: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6094
Polymers54,8442
Non-polymers7652
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase / Cholestenol Delta-isomerase / Delta(8)-Delta(7) sterol isomerase / D8-D7 sterol isomerase / ...Cholestenol Delta-isomerase / Delta(8)-Delta(7) sterol isomerase / D8-D7 sterol isomerase / Emopamil-binding protein / EBP


Mass: 27421.871 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EBP / Production host: Homo sapiens (human) / References: UniProt: Q15125, cholestenol Delta-isomerase
#2: Chemical ChemComp-A1AEU / 1-methyl-1'-[(oxan-4-yl)methyl]-5-(trifluoromethyl)spiro[indole-2,4'-piperidin]-3(1H)-one


Mass: 382.420 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H25F3N2O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: EBP complexed with compound 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 64.009 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 146883 / Symmetry type: POINT

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