4YM9
Crystal structure of Porcine Pancreatic Elastase (PPE) in complex with the novel inhibitor JM102
Summary for 4YM9
| Entry DOI | 10.2210/pdb4ym9/pdb |
| Descriptor | Chymotrypsin-like elastase family member 1, 2-ethyl-2-(hydroxymethyl)-N-(6-methylpyridin-3-yl)butanamide, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | porcine pancreatic elastase, inhibitor, hydrolase |
| Biological source | Sus scrofa (Pig) |
| Total number of polymer chains | 1 |
| Total formula weight | 27055.95 |
| Authors | Hofbauer, S.,Brito, J.A.,Mulchande, J.,Nogly, P.,Pessanha, M.,Moreira, R.,Archer, M. (deposition date: 2015-03-06, release date: 2016-06-29, Last modification date: 2024-10-16) |
| Primary citation | Ruivo, E.F.,Goncalves, L.M.,Carvalho, L.A.,Guedes, R.C.,Hofbauer, S.,Brito, J.A.,Archer, M.,Moreira, R.,Lucas, S.D. Clickable 4-Oxo-beta-lactam-Based Selective Probing for Human Neutrophil Elastase Related Proteomes. ChemMedChem, 11:2037-2042, 2016 Cited by PubMed Abstract: Human neutrophil elastase (HNE) is a serine protease associated with several inflammatory processes such as chronic obstructive pulmonary disease (COPD). The precise involvement of HNE in COPD and other inflammatory disease mechanisms has yet to be clarified. Herein we report a copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC, or 'click' chemistry) approach based on the 4-oxo-β-lactam warhead that yielded potent HNE inhibitors containing a triazole moiety. The resulting structure-activity relationships set the basis to develop fluorescent and biotinylated activity-based probes as tools for molecular functional analysis. Attaching the tags to the 4-oxo-β-lactam scaffold did not affect HNE inhibitory activity, as revealed by the IC50 values in the nanomolar range (56-118 nm) displayed by the probes. The nitrobenzoxadiazole (NBD)-based probe presented the best binding properties (ligand efficiency (LE)=0.31) combined with an excellent lipophilic ligand efficiency (LLE=4.7). Moreover, the probes showed adequate fluorescence properties, internalization in human neutrophils, and suitable detection of HNE in the presence of a large excess of cell lysate proteins. This allows the development of activity-based probes with promising applications in target validation and identification, as well as diagnostic tools. PubMed: 27465595DOI: 10.1002/cmdc.201600258 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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