BCDIN3 domain containing RNA methyltransferase, BCDIN3D, monomethylates the 5'-monophosphate of cytoplasmic tRNAHis with a G-1:A73 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 tRNAHis and for tRNAHis recognition by BCDIN3D. A structural model of tRNAHis 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:A73 mispair in tRNAHis allows the N-terminal α-helix of BCDIN3D to wedge the G-1:A73 mispair of tRNAHis. As a result, the 5'-monophosphate of G-1 of tRNAHis is deep in the catalytic pocket for 5'-phosphate methylation. Thus, BCDIN3D is a tRNAHis-specific 5'-monomethylphosphate capping enzyme that discriminates tRNAHis 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.

中文翻译：

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人类细胞质tRNAHis特异性5'-单甲基磷酸加帽酶的晶体结构。

含BCDIN3结构域的RNA甲基转移酶BCDIN3D使用S-腺苷-1-甲硫氨酸（SAM）作为单核苷酸，在一个8个核苷酸长的受体螺旋的顶部以G-1：A73错配对细胞质tRNAHis的5'-单磷酸进行甲基化。甲基供体。在人类中，BCDIN3D的过表达与肿瘤的致癌表型和预后不良有关。在这里，我们介绍与S-腺苷-1-同型半胱氨酸复合的人BCDIN3D的晶体结构。BCDIN3D采用经典的Rossmann折叠甲基转移酶结构。与密切相关的甲基磷酸加帽酶MePCE进行结构比较，MePCE对7SK RNA的5'-γ-磷酸进行单甲基化，揭示了从SAM转移到tRNAHis的5'-单磷酸以及tRNAHis的重要残基。被BCDIN3D认可。tRNAHis停靠在BCDIN3D上的结构模型表明了BCDIN3D和MePCE之间不同活性的潜在分子机制。与形成α-螺旋以识别MePCE中RNA的5'端的相应区域相比，BCDIN3D中的环更短，而tRNAHis中的G-1：A73错配使N末端的α-螺旋与BCDIN3D消除了tRNAHis的G-1：A73错配。结果，tRNAHis的G-1的5'-单磷酸在5'-磷酸甲基化的催化口袋中很深。因此，BCDIN3D是一种tRNAHis特异的5'-单甲基磷酸加帽酶，可将tRNAHis与其他tRNA种类区分开，本研究中提供的结构信息也为开发抗乳腺癌药物提供了分子基础。