4Z2G

Serratia marcescens Chitinase B complexed with macrolide inhibitor 26

4Z2G の概要

• エントリーDOI: 10.2210/pdb4z2g/pdb
• 関連するPDBエントリー: 3WD0 4Z2H 4Z2I 4Z2J 4Z2K 4Z2L
• 分子名称: Chitinase B, (1R,2R,3R,6R,7S,8S,9R,10R,12R,13S,17S)-3-ethyl-2,10-dihydroxy-2,6,8,10,12,15,15,17-octamethyl-5-oxo-9-(prop-2-yn-1-yloxy)-4,14,16-trioxabicyclo[11.3.1]heptadec-7-yl {4-[N'-(methylcarbamoyl)carbamimidamido]butyl}carbamate (3 entities in total)
• 機能のキーワード: chitinase, inhibitor, macrolide, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Serratia marcescens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57349.17

構造登録者

Maita, N.,Sugawara, A.,Sunazuka, T. (登録日: 2015-03-30, 公開日: 2015-07-01, 最終更新日: 2024-10-30)

主引用文献

Sugawara, A.,Maita, N.,Gouda, H.,Yamamoto, T.,Hirose, T.,Kimura, S.,Saito, Y.,Nakano, H.,Kasai, T.,Nakano, H.,Shiomi, K.,Hirono, S.,Watanabe, T.,Taniguchi, H.,Omura, S.,Sunazuka, T.
Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase
J.Med.Chem., 58:4984-4997, 2015

PubMed Abstract: Argifin, a 17-membered pentapeptide, inhibits chitinase. As argifin has properties that render it unsuitable as a drug development candidate, we devised a mechanism to create the structural component of argifin that bestows the chitinase inhibition and introduce it into a 14-membered macrolide scaffold. Here we describe (1) the designed macrolide, which exhibits ∼200-fold more potent chitinase inhibition than argifin, (2) the binding modes of the macrolide with Serratia marcescens chitinase B, and (3) the computed analysis explaining the reason for derivatives displaying increased inhibition compared to argifin, the macrolide aglycone displaying inhibition in a nanomolar range. This promises a class of chitinase inhibitors with novel skeletons, providing innovative insight for drug design and the use of macrolides as adaptable, flexible templates for use in drug discovery research and development.

PubMed: 26030312
DOI: 10.1021/acs.jmedchem.5b00175

実験手法

X-RAY DIFFRACTION (2.6 Å)