5O48

P.vivax NMT with an aminomethylindazole inhibitor bound

5O48 の概要

• エントリーDOI: 10.2210/pdb5o48/pdb
• 関連するPDBエントリー: 5O4V
• 分子名称: Glycylpeptide N-tetradecanoyltransferase, 2-oxopentadecyl-CoA, 1-[5-(4-fluoranyl-2-methyl-phenyl)-1~{H}-indazol-3-yl]-~{N},~{N}-dimethyl-methanamine, ... (8 entities in total)
• 機能のキーワード: transferase, inhibitor, myristoyl
• 由来する生物種: Plasmodium vivax
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 140193.04

構造登録者

Brannigan, J.A.,Wilkinson, A.J. (登録日: 2017-05-26, 公開日: 2018-05-16, 最終更新日: 2024-05-08)

主引用文献

Mousnier, A.,Bell, A.S.,Swieboda, D.P.,Morales-Sanfrutos, J.,Perez-Dorado, I.,Brannigan, J.A.,Newman, J.,Ritzefeld, M.,Hutton, J.A.,Guedan, A.,Asfor, A.S.,Robinson, S.W.,Hopkins-Navratilova, I.,Wilkinson, A.J.,Johnston, S.L.,Leatherbarrow, R.J.,Tuthill, T.J.,Solari, R.,Tate, E.W.
Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus.
Nat Chem, 10:599-606, 2018

PubMed Abstract: Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.

PubMed: 29760414
DOI: 10.1038/s41557-018-0039-2

実験手法

X-RAY DIFFRACTION (1.69 Å)