1NME

Structure of Casp-3 with tethered salicylate

Summary for 1NME

• Entry DOI: 10.2210/pdb1nme/pdb
• Related: 1NMQ 1NMS
• Descriptor: Caspase-3, 3-(2-MERCAPTO-ACETYLAMINO)-4-OXO-PENTANOIC ACID, 2-HYDROXY-5-(2-MERCAPTO-ETHYLSULFAMOYL)-BENZOIC ACID, ... (5 entities in total)
• Functional Keywords: cysteine proteinase; sulfonamide inhibition, apoptosis, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P42574 P42574
• Total number of polymer chains: 2
• Total formula weight: 27871.85

Authors

Erlanson, D.A.,Lam, J.,Wiesmann, C.,Luong, T.N.,Simmons, B.,DeLano, W.,Choong, I.C.,Flanagan, M.,Lee, D.,O'Brian, T. (deposition date: 2003-01-09, release date: 2003-03-11, Last modification date: 2023-08-16)

Primary citation

Erlanson, D.A.,Lam, J.W.,Wiesmann, C.,Luong, T.N.,Simmons, R.L.,DeLano, W.L.,Choong, I.C.,Burdett, M.T.,Flanagan, W.M.,Lee, D.,Gordon, E.M.,O'Brien, T.
In situ assembly of enzyme inhibitors using extended tethering.
Nat.Biotechnol., 21:308-314, 2003

PubMed Abstract: Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.

PubMed: 12563278
DOI: 10.1038/nbt786

Experimental method

X-RAY DIFFRACTION (1.6 Å)