5E1M

Crystal structure of NTMT1 in complex with PPKRIA peptide

5E1M の概要

• エントリーDOI: 10.2210/pdb5e1m/pdb
• 関連するPDBエントリー: 5E1B 5E1D 5E1O 5E2A 5E2B
• 分子名称: N-terminal Xaa-Pro-Lys N-methyltransferase 1, RCC1, S-ADENOSYL-L-HOMOCYSTEINE, ... (6 entities in total)
• 機能のキーワード: structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : Q9BV86
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 57050.96

構造登録者

Dong, C.,Tempel, W.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Min, J.,Structural Genomics Consortium (SGC) (登録日: 2015-09-29, 公開日: 2015-10-28, 最終更新日: 2024-03-06)

主引用文献

Dong, C.,Mao, Y.,Tempel, W.,Qin, S.,Li, L.,Loppnau, P.,Huang, R.,Min, J.
Structural basis for substrate recognition by the human N-terminal methyltransferase 1.
Genes Dev., 29:2343-2348, 2015

PubMed Abstract: α-N-terminal methylation represents a highly conserved and prevalent post-translational modification, yet its biological function has remained largely speculative. The recent discovery of α-N-terminal methyltransferase 1 (NTMT1) and its physiological substrates propels the elucidation of a general role of α-N-terminal methylation in mediating DNA-binding ability of the modified proteins. The phenotypes, observed from both NTMT1 knockdown in breast cancer cell lines and knockout mouse models, suggest the potential involvement of α-N-terminal methylation in DNA damage response and cancer development. In this study, we report the first crystal structures of human NTMT1 in complex with cofactor S-adenosyl-L-homocysteine (SAH) and six substrate peptides, respectively, and reveal that NTMT1 contains two characteristic structural elements (a β hairpin and an N-terminal extension) that contribute to its substrate specificity. Our complex structures, coupled with mutagenesis, binding, and enzymatic studies, also present the key elements involved in locking the consensus substrate motif XPK (X indicates any residue type other than D/E) into the catalytic pocket for α-N-terminal methylation and explain why NTMT1 prefers an XPK sequence motif. We propose a catalytic mechanism for α-N-terminal methylation. Overall, this study gives us the first glimpse of the molecular mechanism of α-N-terminal methylation and potentially contributes to the advent of therapeutic agents for human diseases associated with deregulated α-N-terminal methylation.

PubMed: 26543161
DOI: 10.1101/gad.270611.115

実験手法

X-RAY DIFFRACTION (1.75 Å)