4GVU

Lyngbyastatin 7-Porcine Pancreatic Elastase Co-crystal Structure

4GVU の概要

• エントリーDOI: 10.2210/pdb4gvu/pdb
• 関連するBIRD辞書のPRD_ID: PRD_000776
• 分子名称: Chymotrypsin-like elastase family member 1, Lyngbyastatin 7, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: cyanobacteria, elastase, lyngbyastatin 7, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Sus scrofa (pigs,swine,wild boar); 詳細
• 細胞内の位置: Secreted: P00772
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27047.29

構造登録者

Salvador, L.A.,Taori, K.,Biggs, J.S.,Jakoncic, J.,Ostrov, D.,Paul, V.J.,Luesch, H. (登録日: 2012-08-31, 公開日: 2013-02-06, 最終更新日: 2023-09-13)

主引用文献

Salvador, L.A.,Taori, K.,Biggs, J.S.,Jakoncic, J.,Ostrov, D.A.,Paul, V.J.,Luesch, H.
Potent elastase inhibitors from cyanobacteria: structural basis and mechanisms mediating cytoprotective and anti-inflammatory effects in bronchial epithelial cells.
J.Med.Chem., 56:1276-1290, 2013

PubMed Abstract: We discovered new structural diversity to a prevalent, yet medicinally underappreciated, cyanobacterial protease inhibitor scaffold and undertook comprehensive protease profiling to reveal potent and selective elastase inhibition. Structure-activity relationship (SAR) studies and X-ray cocrystal structure analysis allowed a detailed assessment of critical and tunable structural elements. To realize the therapeutic potential of these cyclodepsipeptides, we probed the cellular effects of a novel and representative family member, symplostatin 5 (1), which attenuated the downstream cellular effects of elastase in an epithelial lung airway model system, alleviating clinical hallmarks of chronic pulmonary diseases such as cell death, cell detachment, and inflammation. This compound attenuated the effects of elastase on receptor activation, proteolytic processing of the adhesion protein ICAM-1, NF-κB activation, and transcriptomic changes, including the expression of pro-inflammatory cytokines IL1A, IL1B, and IL8. Compound 1 exhibited activity comparable to the clinically approved elastase inhibitor sivelestat in short-term assays and demonstrated superior sustained activity in longer-term assays.

PubMed: 23350733
DOI: 10.1021/jm3017305

実験手法

X-RAY DIFFRACTION (1.55 Å)