8D58

Crystal structure of human METTL1-WDR4 complex

8D58 の概要

• エントリーDOI: 10.2210/pdb8d58/pdb
• 分子名称: tRNA (guanine-N(7)-)-methyltransferase, tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: cancer protein, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 74004.64

構造登録者

Raj, R.,Babu, K.,Nam, Y. (登録日: 2022-06-04, 公開日: 2023-01-11, 最終更新日: 2023-10-25)

主引用文献

Ruiz-Arroyo, V.M.,Raj, R.,Babu, K.,Onolbaatar, O.,Roberts, P.H.,Nam, Y.
Structures and mechanisms of tRNA methylation by METTL1-WDR4.
Nature, 613:383-390, 2023

PubMed Abstract: Specific, regulated modification of RNAs is important for proper gene expression. tRNAs are rich with various chemical modifications that affect their stability and function. 7-Methylguanosine (mG) at tRNA position 46 is a conserved modification that modulates steady-state tRNA levels to affect cell growth. The METTL1-WDR4 complex generates mG46 in humans, and dysregulation of METTL1-WDR4 has been linked to brain malformation and multiple cancers. Here we show how METTL1 and WDR4 cooperate to recognize RNA substrates and catalyse methylation. A crystal structure of METTL1-WDR4 and cryo-electron microscopy structures of METTL1-WDR4-tRNA show that the composite protein surface recognizes the tRNA elbow through shape complementarity. The cryo-electron microscopy structures of METTL1-WDR4-tRNA with S-adenosylmethionine or S-adenosylhomocysteine along with METTL1 crystal structures provide additional insights into the catalytic mechanism by revealing the active site in multiple states. The METTL1 N terminus couples cofactor binding with conformational changes in the tRNA, the catalytic loop and the WDR4 C terminus, acting as the switch to activate mG methylation. Thus, our structural models explain how post-translational modifications of the METTL1 N terminus can regulate methylation. Together, our work elucidates the core and regulatory mechanisms underlying mG modification by METTL1, providing the framework to understand its contribution to biology and disease.

PubMed: 36599982
DOI: 10.1038/s41586-022-05565-5

実験手法

X-RAY DIFFRACTION (2.47 Å)