Structural basis for substrate recognition by the human N-terminal methyltransferase 1.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• α-N-terminal methylation is a widespread post-translational modification with unclear biological roles.
• The enzyme α-N-terminal methyltransferase 1 (NTMT1) and its substrates have been recently identified.
• This modification may influence DNA-binding capabilities of proteins.

Purpose of the Study:

• To elucidate the molecular mechanism and structural basis of α-N-terminal methylation by NTMT1.
• To understand the substrate specificity of NTMT1.
• To provide a foundation for developing therapeutics targeting diseases linked to aberrant methylation.

Main Methods:

• X-ray crystallography of human NTMT1 complexes.
• Mutagenesis studies.
• Binding and enzymatic assays.

Main Results:

• Determined crystal structures of NTMT1 with cofactor SAH and substrate peptides.
• Identified structural elements (β hairpin, N-terminal extension) governing substrate specificity.
• Characterized the interaction of the XPK motif with the NTMT1 catalytic pocket.
• Proposed a catalytic mechanism for α-N-terminal methylation.

Conclusions:

• The study provides the first structural and mechanistic insights into α-N-terminal methylation.
• NTMT1's structure explains its preference for the XPK motif.
• Findings may aid in developing therapies for diseases involving dysregulated α-N-terminal methylation, potentially including cancer.