Structural basis of promiscuous substrate transport by Organic Cation Transporter 1

Area of Science:

• Biochemistry and structural biology
• Pharmacology and drug discovery

Background:

• Organic Cation Transporter 1 (OCT1) is vital for hepatic drug and metabolite uptake.
• Genetic variations in OCT1 impact drug efficacy and safety across various therapeutic areas.
• Understanding OCT1's substrate selectivity and transport mechanisms is crucial for drug development.

Purpose of the Study:

• To elucidate the structural mechanisms underlying OCT1's broad substrate recognition.
• To provide molecular insights into the alternating access transport mechanism of OCT1.
• To explain the structural basis for OCT1's promiscuous drug binding.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structures of full-length human OCT1.
• Structures were obtained in both ligand-free and drug-bound states, capturing the inward-open conformation.
• Comparative structural analysis with outward-open OCTs was performed.

Main Results:

• The cryo-EM structures reveal the inward-open conformation of human OCT1.
• Hydrophobic gates were identified as key stabilizers of the inward-facing state.
• Charge neutralization within the binding pocket was observed to facilitate cationic substrate release.
• The structures provide a molecular basis for OCT1's broad substrate recognition.

Conclusions:

• The study reveals the structural determinants of OCT1's substrate selectivity and transport.
• These findings offer a molecular framework for understanding drug interactions with OCT1.
• The insights gained can aid in the rational design of drugs targeting OCT1.