5V6U

Crystal structure of human caspase-7 soaked with allosteric inhibitor 2-[(2-acetylphenyl)sulfanyl]benzoic acid

Summary for 5V6U

• Entry DOI: 10.2210/pdb5v6u/pdb
• Related: 5V6Z
• Descriptor: Caspase-7, 2-[(2-acetylphenyl)sulfanyl]benzoic acid (3 entities in total)
• Functional Keywords: hydrolase, protease, inhibitor, allosteric, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P55210
• Total number of polymer chains: 2
• Total formula weight: 68919.98

Authors

Vance, N.R.,Gakhar, L.,Spies, M.A. (deposition date: 2017-03-17, release date: 2017-10-18, Last modification date: 2024-10-23)

Primary citation

Vance, N.R.,Gakhar, L.,Spies, M.A.
Allosteric Tuning of Caspase-7: A Fragment-Based Drug Discovery Approach.
Angew. Chem. Int. Ed. Engl., 56:14443-14447, 2017

PubMed Abstract: The caspase family of cysteine proteases are highly sought-after drug targets owing to their essential roles in apoptosis, proliferation, and inflammation pathways. High-throughput screening efforts to discover inhibitors have gained little traction. Fragment-based screening has emerged as a powerful approach for the discovery of innovative drug leads. This method has become a central facet of drug discovery campaigns in the pharmaceutical industry and academia. A fragment-based drug discovery campaign against human caspase-7 resulted in the discovery of a novel series of allosteric inhibitors. An X-ray crystal structure of caspase-7 bound to a fragment hit and a thorough kinetic characterization of a zymogenic form of the enzyme were used to investigate the allosteric mechanism of inhibition. This work further advances our understanding of the mechanisms of allosteric control of this class of pharmaceutically relevant enzymes, and provides a new path forward for drug discovery efforts.

PubMed: 28940929
DOI: 10.1002/anie.201706959

Experimental method

X-RAY DIFFRACTION (2.8 Å)