Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition

Tao Long, Abdirahman Hassan, Bonne M. Thompson, Jeffrey G. McDonald, Jiawei Wang, Xiaochun Li

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacologically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder.

Original languageEnglish (US)
Article number2452
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

human EBP protein
biosynthesis
Biosynthesis
cholesterol
Carrier Proteins
Cholesterol
proteins
Isomerases
Chondrodysplasia Punctata
drugs
Pharmaceutical Preparations
Hydroxysteroids
Anticholesteremic Agents
Mutagenesis
Oligodendroglia
Autophagy
Protein Biosynthesis
Sterols
Tamoxifen
Isomerization

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition. / Long, Tao; Hassan, Abdirahman; Thompson, Bonne M.; McDonald, Jeffrey G.; Wang, Jiawei; Li, Xiaochun.

In: Nature communications, Vol. 10, No. 1, 2452, 01.12.2019.

Research output: Contribution to journalArticle

Long, Tao ; Hassan, Abdirahman ; Thompson, Bonne M. ; McDonald, Jeffrey G. ; Wang, Jiawei ; Li, Xiaochun. / Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition. In: Nature communications. 2019 ; Vol. 10, No. 1.
@article{92fd5a00c6514afca4809b3791fc172c,
title = "Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition",
abstract = "3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacologically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder.",
author = "Tao Long and Abdirahman Hassan and Thompson, {Bonne M.} and McDonald, {Jeffrey G.} and Jiawei Wang and Xiaochun Li",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41467-019-10279-w",
language = "English (US)",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition

AU - Long, Tao

AU - Hassan, Abdirahman

AU - Thompson, Bonne M.

AU - McDonald, Jeffrey G.

AU - Wang, Jiawei

AU - Li, Xiaochun

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacologically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder.

AB - 3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacologically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder.

UR - http://www.scopus.com/inward/record.url?scp=85066936633&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066936633&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-10279-w

DO - 10.1038/s41467-019-10279-w

M3 - Article

C2 - 31165728

AN - SCOPUS:85066936633

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2452

ER -