Molecular basis for histidine N1 position-specific methylation by CARNMT1

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To this end, we first determined the binary crystal structure of human CARNMT1 (aa 53–409) bound to methyl donor S-(5’-Adenosyl)-L-methionine (SAM) at 2.25 Å (Supplementary information, Table S1). CARNMT1 adopts a canonical SAM-MTase (SAM-dependent methyltransferase) core fold consisting of a seven-stranded β sheet (β1-β7) adjoined by six flanking α helices (α1-α6) (Fig. 1b). The SAM cofactor binds to a central cleft formed by the topological switch-point elements next to β1 (Fig. 1c). The SAM binding site is characteristic of a “GxGxG” (G₂₀₈-A₂₀₉-G₂₁₀-L₂₀₉-G₂₁₂) nucleotide-binding motif linking β1 and α2 (Supplementary information, Figure S1A); and SAM forms extensive hydrogen bonding interactions with surrounding residues that are structurally conserved between yeast and human (Supplementary information, Figure S1B).⁸ The enzyme also has several additional structural elements, including four helices (αA, αB, αC and αD) from the N-terminus and an extended β hairpin (β1’, β2’ and αE) inserted between β2 and β3 within the core domain (Fig. 1b, c). These additional structural elements are often divergent among SAM-MTase family members and usually account for the methylation substrate specificity. Structural and SEC-MALS (size exclusion chromatography followed by multi-angle light scattering) analyses revealed that CARNMT1 functions as a symmetric dimer (Supplementary information, Figure S1C and D). The dimer is notably stabilized by anti-parallel β sheet (β7/β7’) formation around the symmetry center and helix bundle contacts among α6 and αA’-αB’-αC’.

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