+
Open data
-
Basic information
Entry | Database: PDB / ID: 8w0s | ||||||
---|---|---|---|---|---|---|---|
Title | Human EBP complexed with compound 3a | ||||||
![]() | 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase | ||||||
![]() | ISOMERASE/INHIBITOR / Emopamil-Binding Protein Isomerization Protein structure complex / STRUCTURAL PROTEIN / ISOMERASE-INHIBITOR complex | ||||||
Function / homology | ![]() 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 / cytoplasmic vesicle / nuclear membrane / endoplasmic reticulum membrane / endoplasmic reticulum / identical protein binding Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å | ||||||
![]() | Sun, D. / Masureel, M. | ||||||
Funding support | 1items
| ||||||
![]() | ![]() 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 |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 116 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
---|
-Related structure data
Related structure data | ![]() 43713MC ![]() 8w0rC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
#1: Protein | Mass: 27421.871 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #2: Chemical | Mass: 425.445 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H26F3N3O3 / Feature type: SUBJECT OF INVESTIGATION Has ligand of interest | Y | |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-
Sample preparation
Component | Name: Human EBP complexed with compound 3a / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
---|---|
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE / Humidity: 100 % |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 64.009 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-
Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
---|---|
3D reconstruction | Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 96963 / Symmetry type: POINT |