NSUN6 inhibitor discovery guided by its mRNA substrate bound crystal structure

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• NSUN6 catalyzes mRNA methylation, a process crucial for transcription.
• Aberrant NSUN6 activity is linked to the oncogenesis of various cancers.

Purpose of the Study:

• To determine the crystal structure of human NSUN6 in complex with its S-adenosyl-L-methionine (SAM) analog and an RNA substrate.
• To elucidate the molecular mechanisms of NSUN6-mediated mRNA methylation and substrate recognition.
• To identify potential NSUN6 inhibitors for cancer therapy.

Main Methods:

• X-ray crystallography at 2.9 Å resolution.
• Nuclear Magnetic Resonance (NMR)-based fragment screening.
• Virtual screening and biochemical verification.

Main Results:

• The crystal structure revealed how NSUN6 recognizes the CUC[CU]A consensus motif in the NECT-2 3'-UTR RNA substrate.
• The study detailed the facilitation of methyl transfer from SAM to mRNA by NSUN6.
• Thiamine disulfide was identified as a lead compound that competes with the substrate for NSUN6 binding.

Conclusions:

• Structural insights into NSUN6-RNA interaction provide a basis for understanding its catalytic mechanism.
• Thiamine disulfide represents a promising non-SAM analog for developing NSUN6 inhibitors.
• These findings offer a foundation for future drug discovery targeting NSUN6-dependent cancers.