9WPY

cryo-EM structure of human organic solute transporter in complex with DHEAS

Summary for 9WPY

• Entry DOI: 10.2210/pdb9wpy/pdb
• EMDB information: 66153
• Descriptor: Organic solute transporter subunit alpha, Organic solute transporter subunit beta, CHOLESTEROL, ... (6 entities in total)
• Functional Keywords: dheas, transporter, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 117014.31

Authors

Sun, X.,Yao, D.,Xue, J. (deposition date: 2025-09-10, release date: 2026-06-10, Last modification date: 2026-10-07)

Primary citation

Sun, X.,Tian, T.,Low, M.,Li, S.,Yao, D.,Yuan, Y.,Cao, M.,Lei, M.,Wang, Y.,Chen, H.,Lan, P.,Xia, Q.,Xue, J.
Structural insights into OST alpha / beta-mediated transport of bile acids and steroid conjugates.
Nat.Struct.Mol.Biol., 33:1288-1298, 2026

PubMed Abstract: 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.

PubMed: 42304113
DOI: 10.1038/s41594-026-01825-4

Experimental method

ELECTRON MICROSCOPY (2.99 Å)