5T5G

human SETD8 in complex with MS2177

5T5G の概要

• エントリーDOI: 10.2210/pdb5t5g/pdb
• 分子名称: N-lysine methyltransferase KMT5A, UNKNOWN ATOM OR ION, 7-(2-aminoethoxy)-6-methoxy-2-(pyrrolidin-1-yl)-N-[5-(pyrrolidin-1-yl)pentyl]quinazolin-4-amine, ... (4 entities in total)
• 機能のキーワード: structural genomics, structural genomics consortium, sgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: Q9NQR1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 17223.47

構造登録者

Yu, W.,Tempel, W.,Babault, N.,Ma, A.,Butler, K.V.,Jin, J.,Arrowsmith, C.H.,Bountra, C.,Edwards, A.M.,Brown, P.J.,Structural Genomics Consortium (SGC) (登録日: 2016-08-30, 公開日: 2016-09-28, 最終更新日: 2024-10-16)

主引用文献

Butler, K.V.,Ma, A.,Yu, W.,Li, F.,Tempel, W.,Babault, N.,Pittella-Silva, F.,Shao, J.,Wang, J.,Luo, M.,Vedadi, M.,Brown, P.J.,Arrowsmith, C.H.,Jin, J.
Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.
J. Med. Chem., 59:9881-9889, 2016

PubMed Abstract: Selective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases. We also solved the crystal structure of the covalent inhibitor in complex with SETD8. This work provides atomic-level perspective on the inhibition of SETD8 by small molecules and will help identify high-quality chemical probes of SETD8.

PubMed: 27804297
DOI: 10.1021/acs.jmedchem.6b01244

実験手法

X-RAY DIFFRACTION (2.1 Å)