3RM4

AMCase in complex with Compound 1

3RM4 の概要

• エントリーDOI: 10.2210/pdb3rm4/pdb
• 関連するPDBエントリー: 3RM8 3RM9 3RME
• 分子名称: Acidic mammalian chitinase, 5-{4-[2-(4-bromophenoxy)ethyl]piperazin-1-yl}-4H-1,2,4-triazol-3-amine (3 entities in total)
• 機能のキーワード: hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted. Isoform 2: Cytoplasm. Isoform 3: Cytoplasm: Q9BZP6
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 89141.23

構造登録者

Olland, A. (登録日: 2011-04-20, 公開日: 2011-08-24, 最終更新日: 2024-10-16)

主引用文献

Cole, D.C.,Olland, A.M.,Jacob, J.,Brooks, J.,Bursavich, M.G.,Czerwinski, R.,Declercq, C.,Johnson, M.,Joseph-McCarthy, D.,Ellingboe, J.W.,Lin, L.,Nowak, P.,Presman, E.,Strand, J.,Tam, A.,Williams, C.M.M.,Yao, S.,Tsao, D.H.H.,Fitz, L.J.
Identification and Characterization of Acidic Mammalian Chitinase Inhibitors
J.Med.Chem., 53:6122-6128, 2010

PubMed Abstract: Acidic mammalian chitinase (AMCase) is a member of the glycosyl hydrolase 18 family (EC 3.2.1.14) that has been implicated in the pathophysiology of allergic airway disease such as asthma. Small molecule inhibitors of AMCase were identified using a combination of high-throughput screening, fragment screening, and virtual screening techniques and characterized by enzyme inhibition and NMR and Biacore binding experiments. X-ray structures of the inhibitors in complex with AMCase revealed that the larger more potent HTS hits, e.g. 5-(4-(2-(4-bromophenoxy)ethyl)piperazine-1-yl)-1H-1,2,4-triazol-3-amine 1, spanned from the active site pocket to a hydrophobic pocket. Smaller fragments identified by FBS occupy both these pockets independently and suggest potential strategies for linking fragments. Compound 1 is a 200 nM AMCase inhibitor which reduced AMCase enzymatic activity in the bronchoalveolar lavage fluid in allergen-challenged mice after oral dosing.

PubMed: 20666458

実験手法

X-RAY DIFFRACTION (1.9 Å)