Structural modeling of human organic cation transporters

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Human organic cation transporters (hOCTs), part of the solute carrier (SLC) 22 family, are vital membrane proteins involved in transporting chemotherapeutic drugs.
• Dysregulation of hOCTs is implicated in various conditions, including cancer and diabetes.
• Understanding hOCTs' drug-binding and transport mechanisms is crucial but hindered by the lack of crystal structures.

Purpose of the Study:

• To compute high-resolution 3D structural models for seven human organic cation transporters (hOCTs) using a multi-phasic in-silico approach.
• To provide structural insights into the function of hOCTs as drug transporters.
• To facilitate further research into the mechanisms of drug binding and transport by hOCTs.

Main Methods:

• Comparative sequence alignment, threading, and ab-initio protein modeling using I-TASSER.
• Secondary structure prediction with PSIPRED and loop modeling in Chimera.
• Structure refinement, energy minimization with ModRefiner, and validation using PROCHECK at SAVEs.

Main Results:

• Computed 3D structural models of seven hOCTs, revealing a typical major facilitator superfamily (MFS) fold with twelve α-transmembrane helices.
• Modeled structures resemble human SLC2A3 (GLUT3) transporter, exhibiting an outward-open conformation and putative C1 symmetry.
• Identified unique extracellular loops with potential glycosylation and cysteine sites, and intracellular loops with putative phosphorylation sites, suggesting roles in drug interaction and regulation.

Conclusions:

• The in-silico computed 3D structural models of hOCTs offer valuable structural information in the absence of experimental crystal structures.
• These models can serve as a foundation for investigating the precise mechanisms of drug binding and transport mediated by hOCTs.
• The findings pave the way for structure-based drug design targeting hOCTs for various diseases.