The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors

Area of Science:

• Biochemistry
• Structural Biology
• Cancer Biology

Background:

• Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a key enzyme in 1-carbon metabolism, highly upregulated in cancer and a promising anticancer target.
• Selective MTHFD2 inhibition could minimize side effects associated with antifolate drugs targeting other 1-carbon metabolism enzymes.
• Developing selective inhibitors is difficult due to high sequence identity between MTHFD2 and its isoforms, MTHFD1 and MTHFD2L.

Purpose of the Study:

• To determine the structure of MTHFD2L, an isoform of MTHFD2.
• To elucidate the structural basis for the inhibition of MTHFD2L by the potent MTHFD2 inhibitor TH7299.
• To highlight the challenges in developing isoform-selective MTHFD2 inhibitors.

Main Methods:

• X-ray crystallography was used to determine the structure of MTHFD2L.
• The structure of the MTHFD2L-TH7299 complex was determined.
• Comparative structural analysis of MTHFD2, MTHFD1, and MTHFD2L was performed.

Main Results:

• The first structure of MTHFD2L was determined.
• The structure of the MTHFD2L-TH7299 complex revealed the molecular interactions responsible for TH7299's potent MTHFD2L inhibition.
• Structural analysis highlighted significant challenges in achieving isoform selectivity for MTHFD2 inhibitors.

Conclusions:

• The determined MTHFD2L structure provides critical insights into inhibitor binding and isoform selectivity.
• Achieving truly selective MTHFD2 inhibition requires careful consideration of structural differences between MTHFD2 and its isoforms.
• This structural information is vital for the rational design of next-generation anticancer therapeutics targeting MTHFD2.