+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-43713 | |||||||||
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Title | Human EBP complexed with compound 3a | |||||||||
Map data | ||||||||||
Sample |
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Keywords | 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 / cytoplasmic vesicle / nuclear membrane / endoplasmic reticulum membrane / endoplasmic reticulum / identical protein binding Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.8 Å | |||||||||
Authors | Sun D / Masureel M | |||||||||
Funding support | 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_43713.map.gz | 229.8 MB | EMDB map data format | |
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Header (meta data) | emd-43713-v30.xml emd-43713.xml | 16.9 KB 16.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_43713_fsc.xml | 13.1 KB | Display | FSC data file |
Images | emd_43713.png | 108.9 KB | ||
Filedesc metadata | emd-43713.cif.gz | 5.6 KB | ||
Others | emd_43713_additional_1.map.gz emd_43713_half_map_1.map.gz emd_43713_half_map_2.map.gz | 123 MB 226 MB 226 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-43713 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-43713 | HTTPS FTP |
-Validation report
Summary document | emd_43713_validation.pdf.gz | 1004.3 KB | Display | EMDB validaton report |
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Full document | emd_43713_full_validation.pdf.gz | 1003.9 KB | Display | |
Data in XML | emd_43713_validation.xml.gz | 22.1 KB | Display | |
Data in CIF | emd_43713_validation.cif.gz | 28.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-43713 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-43713 | HTTPS FTP |
-Related structure data
Related structure data | 8w0sMC 8w0rC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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-Map
File | Download / File: emd_43713.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.93856 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: #1
File | emd_43713_additional_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_43713_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_43713_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Human EBP complexed with compound 3a
Entire | Name: Human EBP complexed with compound 3a |
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Components |
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-Supramolecule #1: Human EBP complexed with compound 3a
Supramolecule | Name: Human EBP complexed with compound 3a / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase
Macromolecule | Name: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 27.421871 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: 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 |
-Macromolecule #2: 1-methyl-8-[(oxan-4-yl)methyl]-3-[4-(trifluoromethyl)phenyl]-1,3,...
Macromolecule | Name: 1-methyl-8-[(oxan-4-yl)methyl]-3-[4-(trifluoromethyl)phenyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione type: ligand / ID: 2 / Number of copies: 2 / Formula: A1AEV |
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Molecular weight | Theoretical: 425.445 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.009 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |