Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power

Kathryn F. Hobbs; Jonah Propp; Nicholas R. Vance; Andrew Kalenkiewicz; Katie R. Witkin; M. Ashley Spies

doi:10.1002/chem.202300872

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Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power

Journal article

Open access

Peer reviewed

Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power

Kathryn F. Hobbs, Jonah Propp, Nicholas R. Vance, Andrew Kalenkiewicz, Katie R. Witkin and M. Ashley Spies

Chemistry : a European journal, Vol.29(40), e202300872

05/19/2023

DOI: 10.1002/chem.202300872

PMCID: PMC11596327

PMID: 37005499

Appears in UI Libraries Support Open Access

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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).

Physical Sciences

Chemistry

Chemistry, Multidisciplinary

Science & Technology

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Details

Title: Subtitle: Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power
Creators: Kathryn F. Hobbs - University of Iowa, Pharmaceutical Sciences and Experimental Therapeutics
Jonah Propp - University of Iowa
Nicholas R. Vance - University of Iowa
Andrew Kalenkiewicz - University of Iowa
Katie R. Witkin - University of Iowa
M. Ashley Spies - University of Iowa, Medicinal and Natural Products Chemistry
Resource Type: Journal article
Publication Details: Chemistry : a European journal, Vol.29(40), e202300872
DOI: 10.1002/chem.202300872
PMID: 37005499
PMCID: PMC11596327
NLM abbreviation: Chemistry
ISSN: 0947-6539
eISSN: 1521-3765
Publisher: Wiley
Number of pages: 10
Grant note: R01-GM09737; R01-GM138471 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32-GM008365 / NIH Predoctoral Training Program in Biotechnology; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA DE-AC02-05CH11231 / DOE Office of Science; United States Department of Energy (DOE) Center for Biocatalysis and Bioprocessing at the University of Iowa DE-AC02-06CH11357 / ALS-ENABLE program - National Institutes of Health (NIH), National Institute of General Medical Sciences
Language: English
Date published: 05/19/2023
Academic Unit: Stead Family Department of Pediatrics; Pharmaceutical Sciences and Experimental Therapeutics; Biochemistry and Molecular Biology; Medicinal and Natural Products Chemistry
Record Identifier: 9984443359502771

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