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TitleStructural insights into OSTα/β-mediated transport of bile acids and steroid conjugates.
Journal, issue, pagesNat Struct Mol Biol, Vol. 33, Issue 9, Page 1288-1298, Year 2026
Publish dateJun 16, 2026
AuthorsXicheng Sun / Taikun Tian / Minying Low / Shaobai Li / Deqiang Yao / Yanmei Yuan / Mi Cao / Ming Lei / Yong Wang / Hongwen Chen / Pengfei Lan / Qiang Xia / Jing Xue /
PubMed AbstractMammalian organic solute transporter α/β (OSTα/β) is crucial for the enterohepatic circulation of bile acids and the homeostasis of steroid conjugates, mediating their movement across membranes ...Mammalian organic solute transporter α/β (OSTα/β) is crucial for the enterohepatic circulation of bile acids and the homeostasis of steroid conjugates, mediating their movement across membranes as an obligate heterodimer. Here we present high-resolution cryo-EM structures of human OSTα/β in apo, substrate-bound and inhibitor-bound states, revealing a tetrameric organization as a homodimer of heterodimers that is required for membrane activity. Substrates bind within a surface-exposed tunnel formed by transmembrane helices 5 and 6, which is unexpectedly sealed by multiple palmitoyl chains covalently attached to a conserved intracellular loop IL2. Two chemically distinct inhibitors, fidaxomicin and ethinylestradiol, disrupt transport by both competing for the substrate-binding pocket and sterically occluding the tunnel. Together with biochemical and evolutionary analyses, our work defines a distinctive class of solute carriers that uses palmitoylation to facilitate substrate transport, a mechanism conserved across eukaryotes.
External linksNat Struct Mol Biol / PubMed:42304113
MethodsEM (single particle)
Resolution2.68 - 3.11 Å
Structure data

66144

9wpl

EMDB-66144, PDB-9wpl:
cryo-EM structure of human organic solute transporter in apo state
Method: EM (single particle) / Resolution: 2.81 Å

66153

9wpy

EMDB-66153, PDB-9wpy:
cryo-EM structure of human organic solute transporter in complex with DHEAS
Method: EM (single particle) / Resolution: 2.99 Å

66155

9wpz

EMDB-66155, PDB-9wpz:
cryo-EM structure of human organic solute transporter in complex with TLCA
Method: EM (single particle) / Resolution: 3.11 Å

66156

9wq0

EMDB-66156, PDB-9wq0:
cryo-EM structure of human organic solute transporter in complex with ethinylestradiol
Method: EM (single particle) / Resolution: 2.68 Å

66180

9wqr

EMDB-66180, PDB-9wqr:
cryo-EM structure of human organic solute transporter in complex with fidaxomicin
Method: EM (single particle) / Resolution: 2.79 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-PLM:
PALMITIC ACID

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

ChemComp-ZWY:
17-oxoandrost-5-en-3beta-yl hydrogen sulfate

PDB-1epx:
CRYSTAL STRUCTURE ANALYSIS OF ALDOLASE FROM L. MEXICANA

ChemComp-3WF:
Ethinyl estradiol / medication, hormone*YM

ChemComp-FI8:
Fidaxomicin / medication, antibiotic*YM

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / apo / TRANSPORTER / DHEAS / TLCA / ethinylestradiol / fidaxomicin

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