9B71

Cryo-EM structure of MraY in complex with analogue 3

これはPDB形式変換不可エントリーです。

9B71 の概要

• エントリーDOI: 10.2210/pdb9b71/pdb
• 関連するPDBエントリー: 9B70
• EMDBエントリー: 44294
• 分子名称: MraYAA Nanobody, Phospho-N-acetylmuramoyl-pentapeptide-transferase, (2~{S},3~{S})-3-[(2~{S},3~{R},4~{S},5~{R})-5-(aminomethyl)-3,4-bis(oxidanyl)oxolan-2-yl]oxy-3-[(2~{S},3~{S},4~{R},5~{R})-5-[2,4-bis(oxidanylidene)pyrimidin-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]-2-[[4-[[[(2~{S})-5-carbamimidamido-2-(hexadecanoylamino)pentanoyl]amino]methyl]phenyl]methylamino]propanoic acid, ... (4 entities in total)
• 機能のキーワード: inhibitor, antibiotics, transferase
• 由来する生物種: Lama glama (llama); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 113948.95

構造登録者

Hao, A.,Lee, S.-Y. (登録日: 2024-03-26, 公開日: 2024-06-26, 最終更新日: 2024-10-23)

主引用文献

Yamamoto, K.,Sato, T.,Hao, A.,Asao, K.,Kaguchi, R.,Kusaka, S.,Ruddarraju, R.R.,Kazamori, D.,Seo, K.,Takahashi, S.,Horiuchi, M.,Yokota, S.I.,Lee, S.Y.,Ichikawa, S.
Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target.
Nat Commun, 15:5085-5085, 2024

PubMed Abstract: MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities.

PubMed: 38877016
DOI: 10.1038/s41467-024-49484-7

実験手法

ELECTRON MICROSCOPY (2.7 Å)