8DJ3

Caspase-7 bound to novel allosteric inhibitor

Summary for 8DJ3

• Entry DOI: 10.2210/pdb8dj3/pdb
• Descriptor: Caspase-7, 2-[(2-{[(3s,5s,7s)-adamantan-1-yl]sulfamoyl}phenyl)sulfanyl]benzoic acid (3 entities in total)
• Functional Keywords: allostery, inhibitor, ternary, apoptosis-apoptosis inhibitor complex, apoptosis/apoptosis inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69575.77

Authors

Propp, J.,Kalenkiewicz, A.,Kathryn, F.H.,Spies, M.A. (deposition date: 2022-06-29, release date: 2023-07-05, Last modification date: 2023-10-25)

Primary citation

Hobbs, K.F.,Propp, J.,Vance, N.R.,Kalenkiewicz, A.,Witkin, K.R.,Ashley Spies, M.
Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power.
Chemistry, 29:e202300872-e202300872, 2023

PubMed Abstract: Caspase-7 (C7), a cysteine protease involved in apoptosis, is a valuable drug target for its role in human diseases (e. g., Parkinson's, Alzheimer's, sepsis). The C7 allosteric site has great potential for small-molecule targeting, but numerous drug discovery efforts have identified precious few allosteric inhibitors. Here we present the first selective, drug-like inhibitor of C7 along with several other improved inhibitors based on our previous fragment hit. We also provide a rational basis for the impact of allosteric binding on the C7 catalytic cycle by using an integrated approach including X-ray crystallography, stopped-flow kinetics, and molecular dynamics simulations. Our findings suggest allosteric binding disrupts C7 pre-acylation by neutralization of the catalytic dyad, displacement of substrate from the oxyanion hole, and altered dynamics of substrate binding loops. This work advances drug targeting efforts and bolsters our understanding of allosteric structure-activity relationships (ASARs).

PubMed: 37005499
DOI: 10.1002/chem.202300872

Experimental method

X-RAY DIFFRACTION (3.2 Å)