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Exploring the S4 and S1 prime subsite specificities in caspase-3 with aza-peptide epoxide inhibitors.

Ganesan R, Jelakovic S, Campbell AJ, Li ZZ, Asgian JL, Powers JC, Grütter MG
Biochemistry 45 9059-67 (2006)
Related entries: 2cdr, 2cnl, 2cnn, 2cno

Cited: 18 times
EuropePMC logo PMID: 16866351

Abstract

Caspase-3 is a prototypic executioner caspase that plays a central role in apoptosis. Aza-peptide epoxides are a novel class of irreversible inhibitors that are highly specific for clan CD cysteine proteases. The five crystal structures of caspase-3-aza-peptide epoxide inhibitor complexes reported here reveal the structural basis for the mechanism of inhibition and the specificities at the S1' and the S4 subsites. Unlike the clan CA cysteine proteases, the catalytic histidine in caspase-3 plays a critical role during protonation and subsequent ring opening of the epoxide moiety and facilitates the nucleophilic attack by the active site cysteine. The nucleophilic attack takes place on the C3 carbon atom of the epoxide and results in an irreversible alkylation of the active site cysteine residue. A favorable network of hydrogen bonds involving the oxyanion hole, catalytic histidine, and the atoms in the prime site of the inhibitor enhance the binding affinity and specificity of the aza-peptide epoxide inhibitors toward caspase-3. The studies also reveal that subtle movements of the N-terminal loop of the beta-subunit occur when the P4 Asp is replaced by a P4 Ile, whereas the N-terminal loop and the safety catch Asp179 are completely disordered when the P4 Asp is replaced by P4 Cbz group.

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  1. Caspase substrates and inhibitors. Poreba M, Strózyk A, Salvesen GS, Drag M. Cold Spring Harb Perspect Biol 5 a008680 (2013)
  2. Targeting cell death in tumors by activating caspases. MacKenzie SH, Clark AC. Curr Cancer Drug Targets 8 98-109 (2008)
  3. Autoproteolytic activation of bacterial toxins. Shen A. Toxins (Basel) 2 963-977 (2010)
  4. Using specificity to strategically target proteases. Lim MD, Craik CS. Bioorg Med Chem 17 1094-1100 (2009)
  5. Crosstalk of the Caspase Family and Mammalian Target of Rapamycin Signaling. Yan J, Xie Y, Si J, Gan L, Li H, Sun C, Di C, Zhang J, Huang G, Zhang X, Zhang H. Int J Mol Sci 22 E817 (2021)

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  1. Mechanistic and structural insights into the proteolytic activation of Vibrio cholerae MARTX toxin. Shen A, Lupardus PJ, Albrow VE, Guzzetta A, Powers JC, Garcia KC, Bogyo M. Nat Chem Biol 5 469-478 (2009)
  2. A peptide-based positron emission tomography probe for in vivo detection of caspase activity in apoptotic cells. Hight MR, Cheung YY, Nickels ML, Dawson ES, Zhao P, Saleh S, Buck JR, Tang D, Washington MK, Coffey RJ, Manning HC. Clin Cancer Res 20 2126-2135 (2014)
  3. In silico identification and crystal structure validation of caspase-3 inhibitors without a P1 aspartic acid moiety. Ganesan R, Jelakovic S, Mittl PR, Caflisch A, Grütter MG. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 842-850 (2011)
  4. A new class of α-ketoamide derivatives with potent anticancer and anti-SARS-CoV-2 activities. Wang J, Liang B, Chen Y, Fuk-Woo Chan J, Yuan S, Ye H, Nie L, Zhou J, Wu Y, Wu M, Huang LS, An J, Warshel A, Yuen KY, Ciechanover A, Huang Z, Xu Y. Eur J Med Chem 215 113267 (2021)
  5. Synthesis of (2S)-2-amino-7,8-epoxyoctanoic acid and structure of its metal-bridging complex with human arginase I. Zakharian TY, Di Costanzo L, Christianson DW. Org Biomol Chem 6 3240-3243 (2008)
  6. Ac-tLeu-Asp-H is the minimal and highly effective human caspase-3 inhibitor: biological and in silico studies. Ferrucci A, Leboffe L, Agamennone M, Di Pizio A, Fiocchetti M, Marino M, Ascenzi P, Luisi G. Amino Acids 47 153-162 (2015)
  7. Exploring the prime site in caspases as a novel chemical strategy for understanding the mechanisms of cell death: a proof of concept study on necroptosis in cancer cells. Groborz K, Gonzalez Ramirez ML, Snipas SJ, Salvesen GS, Drąg M, Poręba M. Cell Death Differ 27 451-465 (2020)
  8. Carboxylate isosteres for caspase inhibitors: the acylsulfonamide case revisited. Adriaenssens Y, Jiménez Fernández D, Vande Walle L, Elvas F, Joossens J, Lambeir A, Augustyns K, Lamkanfi M, Van der Veken P. Org Biomol Chem 15 7456-7473 (2017)
  9. Genetic characterization of two gain-of-function alleles of the effector caspase DrICE in Drosophila. Wu Y, Lindblad JL, Garnett J, Kamber Kaya HE, Xu D, Zhao Y, Flores ER, Hardy J, Bergmann A. Cell Death Differ 23 723-732 (2016)


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