Structural basis of antifolate recognition and transport by PCFT

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Medicine

Background:

• Folates (vitamin B9) are essential for cellular metabolism, including nucleic acid and amino acid synthesis.
• Deficiency in folates can lead to developmental, immune, and neurological disorders.
• Mammals require dietary folates, relying on specialized transport systems like the proton-coupled folate transporter (PCFT).

Purpose of the Study:

• To elucidate the molecular mechanism of folate recognition by PCFT.
• To understand how PCFT interacts with antifolate drugs used in cancer chemotherapy.
• To provide structural insights into the pH-regulated transport function of PCFT.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of PCFT.
• Structures were obtained for PCFT in a substrate-free state and in complex with pemetrexed.
• Analysis focused on the structural basis of antifolate recognition and transport.

Main Results:

• The study presents the cryo-EM structures of PCFT, revealing its molecular architecture.
• Detailed structural information was obtained for PCFT bound to the antifolate drug pemetrexed.
• The findings provide a structural foundation for understanding how PCFT recognizes its substrates.

Conclusions:

• The determined structures offer a mechanistic understanding of antifolate recognition by PCFT.
• Insights into the pH-regulated transport mechanism of PCFT were gained.
• This research provides a basis for developing novel antifolate-based therapies.