4GVU

Lyngbyastatin 7-Porcine Pancreatic Elastase Co-crystal Structure

Summary for 4GVU

• Entry DOI: 10.2210/pdb4gvu/pdb
• Related PRD ID: PRD_000776
• Descriptor: Chymotrypsin-like elastase family member 1, Lyngbyastatin 7, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: cyanobacteria, elastase, lyngbyastatin 7, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Sus scrofa (pigs,swine,wild boar); More
• Cellular location: Secreted: P00772
• Total number of polymer chains: 2
• Total formula weight: 27047.29

Authors

Salvador, L.A.,Taori, K.,Biggs, J.S.,Jakoncic, J.,Ostrov, D.,Paul, V.J.,Luesch, H. (deposition date: 2012-08-31, release date: 2013-02-06, Last modification date: 2023-09-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.55 Å)