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Methotrexate recognition by the human reduced folate carrier SLC19A1.

Nicholas J Wright¹, Justin G Fedor¹, Han Zhang²

¹Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.

|September 7, 2022

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The human reduced folate carrier (hRFC) imports essential folates and chemotherapy drugs. New structures reveal how hRFC recognizes and transports these vital molecules, impacting drug sensitivity.

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Area of Science:

Biochemistry
Molecular Biology
Structural Biology

Background:

Folates are essential nutrients crucial for cell division and amino acid metabolism.
Mammals require extracellular folate uptake, primarily via the human reduced folate carrier (hRFC/SLC19A1).
hRFC imports folates and antifolate drugs like methotrexate, influencing chemotherapy effectiveness.

Purpose of the Study:

To elucidate the molecular mechanisms underlying substrate specificity in hRFC.
To understand how hRFC distinguishes between different folate and antifolate molecules.
To investigate the structural basis of anion recognition by hRFC.

Main Methods:

Cryo-electron microscopy (cryo-EM) to determine hRFC structures.
Molecular dynamics (MD) simulations to analyze transport mechanisms.
Functional experiments to validate structural findings.

Main Results:

Presented high-resolution cryo-EM structures of hRFC in apo and methotrexate-bound states.
Identified key structural determinants governing hRFC's substrate selectivity.
Elucidated the mechanism of anion recognition and transport by hRFC.

Conclusions:

The study provides unprecedented structural insights into hRFC function.
Understanding hRFC selectivity is crucial for optimizing antifolate-based therapies.
This work lays the foundation for future drug development targeting folate transport.