Crystal structure of human cytoplasmic tRNA(His)-specific 5′-monomethylphosphate capping enzyme

BCDIN3 domain containing RNA methyltransferase, BCDIN3D, monomethylates the 5′-monophosphate of cytoplasmic tRNA(His) with a G(−1):A(73) mispair at the top of an eight-nucleotide-long acceptor helix, using S-adenosyl-l-methionine (SAM) as a methyl group donor. In humans, BCDIN3D overexpression is associated with the tumorigenic phenotype and poor prognosis in breast cancer. Here, we present the crystal structure of human BCDIN3D complexed with S-adenosyl-l-homocysteine. BCDIN3D adopts a classical Rossmann-fold methyltransferase structure. A comparison of the structure with that of the closely related methylphosphate capping enzyme, MePCE, which monomethylates the 5′-γ-phosphate of 7SK RNA, revealed the important residues for monomethyl transfer from SAM onto the 5′-monophosphate of tRNA(His) and for tRNA(His) recognition by BCDIN3D. A structural model of tRNA(His) docking onto BCDIN3D suggested the molecular mechanism underlying the different activities between BCDIN3D and MePCE. A loop in BCDIN3D is shorter, as compared to the corresponding region that forms an α-helix to recognize the 5′-end of RNA in MePCE, and the G(−1):A(73) mispair in tRNA(His) allows the N-terminal α-helix of BCDIN3D to wedge the G(−1):A(73) mispair of tRNA(His). As a result, the 5′-monophosphate of G(−1) of tRNA(His) is deep in the catalytic pocket for 5′-phosphate methylation. Thus, BCDIN3D is a tRNA(His)-specific 5′-monomethylphosphate capping enzyme that discriminates tRNA(His) from other tRNA species, and the structural information presented in this study also provides the molecular basis for the development of drugs against breast cancers.