3ibf Citations

Conformational similarity in the activation of caspase-3 and -7 revealed by the unliganded and inhibited structures of caspase-7.

Apoptosis 14 1135-44 (2009)
Cited: 13 times
EuropePMC logo PMID: 19655253

Abstract

Caspase-mediated apoptosis has important roles in normal cell differentiation and aging and in many diseases including cancer, neuromuscular disorders and neurodegenerative diseases. Therefore, modulation of caspase activity and conformational states is of therapeutic importance. We report crystal structures of a new unliganded conformation of caspase-7 and the inhibited caspase-7 with the tetrapeptide Ac-YVAD-Cho. Different conformational states and mechanisms for substrate recognition have been proposed based on unliganded structures of the redundant apoptotic executioner caspase-3 and -7. The current study shows that the executioner caspase-3 and -7 have similar conformations for the unliganded active site as well as the inhibitor-bound active site. The new unliganded caspase-7 structure exhibits the tyrosine flipping mechanism in which the Tyr230 has rotated to block entry to the S2 binding site similar to the active site conformation of unliganded caspase-3. The inhibited structure of caspase-7/YVAD shows that the P4 Tyr binds the S4 region specific to polar residues at the expense of a main chain hydrogen bond between the P4 amide and carbonyl oxygen of caspase-7 Gln 276, which is similar to the caspase-3 complex. This new knowledge of the structures and conformational states of unliganded and inhibited caspases will be important for the design of drugs to modulate caspase activity and apoptosis.

Articles - 3ibf mentioned but not cited (2)

  1. A class of allosteric caspase inhibitors identified by high-throughput screening. Feldman T, Kabaleeswaran V, Jang SB, Antczak C, Djaballah H, Wu H, Jiang X. Mol. Cell 47 585-595 (2012)
  2. Dual Site Phosphorylation of Caspase-7 by PAK2 Blocks Apoptotic Activity by Two Distinct Mechanisms. Eron SJ, Raghupathi K, Hardy JA. Structure 25 27-39 (2017)


Reviews citing this publication (1)

  1. Small Molecule Active Site Directed Tools for Studying Human Caspases. Poreba M, Szalek A, Kasperkiewicz P, Rut W, Salvesen GS, Drag M. Chem. Rev. 115 12546-12629 (2015)

Articles citing this publication (10)

  1. Granulysin delivered by cytotoxic cells damages endoplasmic reticulum and activates caspase-7 in target cells. Saini RV, Wilson C, Finn MW, Wang T, Krensky AM, Clayberger C. J. Immunol. 186 3497-3504 (2011)
  2. Design, construction, and characterization of a second-generation DARP in library with reduced hydrophobicity. Seeger MA, Zbinden R, Flütsch A, Gutte PG, Engeler S, Roschitzki-Voser H, Grütter MG. Protein Sci. 22 1239-1257 (2013)
  3. Studies of the molecular mechanism of caspase-8 activation by solution NMR. Keller N, Grütter MG, Zerbe O. Cell Death Differ. 17 710-718 (2010)
  4. Specificity of a protein-protein interface: local dynamics direct substrate recognition of effector caspases. Fuchs JE, von Grafenstein S, Huber RG, Wallnoefer HG, Liedl KR. Proteins 82 546-555 (2014)
  5. Specific inhibition of caspase-3 by a competitive DARPin: molecular mimicry between native and designed inhibitors. Schroeder T, Barandun J, Flütsch A, Briand C, Mittl PR, Grütter MG. Structure 21 277-289 (2013)
  6. Adenovirus-mediated expression of truncated E2F-1 suppresses tumor growth in vitro and in vivo. Gomez-Gutierrez JG, Garcia-Garcia A, Hao H, Rao XM, Montes de Oca-Luna R, Zhou HS, McMasters KM. Cancer 116 4420-4432 (2010)
  7. Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis. Tang Y, Wells JA, Arkin MR. J. Biol. Chem. 286 34147-34154 (2011)
  8. Cysteinome: The first comprehensive database for proteins with targetable cysteine and their covalent inhibitors. Wu S, Luo Howard H, Wang H, Zhao W, Hu Q, Yang Y. Biochem. Biophys. Res. Commun. 478 1268-1273 (2016)
  9. Combined inhibition of caspase 3 and caspase 7 by two highly selective DARPins slows down cellular demise. Flütsch A, Ackermann R, Schroeder T, Lukarska M, Hausammann GJ, Weinert C, Briand C, Grütter MG. Biochem. J. 461 279-290 (2014)
  10. Molecular insight into the role of the leucine residue on the L2 loop in the catalytic activity of caspases 3 and 7. Kang HJ, Lee YM, Jeong MS, Kim M, Bae KH, Kim SJ, Chung SJ. Biosci. Rep. 32 305-313 (2012)