Related Experiment Video

Updated: Aug 10, 2026

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
08:47

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

The atomic-resolution structure of human caspase-8, a key activator of apoptosis

W Watt1, K A Koeplinger, A M Mildner

  • 1Structural, Analytical & Medicinal Chemistry Pharmacia & Upjohn Inc. 301 Henrietta Street, Kalamazoo, MI 49007, USA.

Structure (London, England : 1993)
|October 6, 1999
PubMed
Abstract

Insights

Caspase-8, an initiator caspase, is crucial for apoptosis. Its structure, determined via X-ray crystallography with an inhibitor, reveals key details for designing drugs to block cell death in degenerative disorders.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Background:

  • Caspases are cysteine proteases vital for inflammation and apoptosis.
  • Caspase-8 initiates downstream caspase activation in apoptotic cascades.
  • Caspase-8 is a therapeutic target for degenerative disorders.

Purpose of the Study:

  • Determine the high-resolution structure of human caspase-8.
  • Analyze the interaction between caspase-8 and its inhibitor acetyl-Ile-Glu-Thr-Asp-aldehyde.
  • Understand structure-function relationships for inhibitor design.

Main Methods:

  • X-ray crystallography
  • Recombinant protein expression
  • Covalent modification with inhibitor

Main Results:

  • The 1.2 Å resolution structure of the caspase-8-inhibitor complex was determined.
  • The biologically active caspase-8 molecule consists of two p18-p11 heterodimers.
  • Significant differences in the substrate-binding region compared to caspase-1 and -3 were observed.

Conclusions:

  • The catalytic triad involves Cys360, His317, and Arg258.
  • The inhibitor's thiohemiacetal group interacts with His317, deviating from a classical oxyanion hole.
  • The determined structure facilitates understanding of caspase-8's role in programmed cell death and inhibitor design.

More Related Videos

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches05:56

Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches

Published on: October 13, 2022

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry05:29

Measuring Caspase Activity Using a Fluorometric Assay or Flow Cytometry

Published on: March 24, 2023

Related Concept Videos

Apoptosis01:30

Apoptosis

Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.
Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
The DNA Helix01:07

The DNA Helix

Deoxyribonucleic acid, or DNA, is the genetic material responsible for passing traits from generation to generation in all organisms and most viruses. DNA is composed of two strands of nucleotides that wind around each other to form a spring-like structure called a double helix. However, the double helix is not perfectly symmetrical. Instead, there are regularly occurring grooves in the structure. The major groove occurs where the sugar-phosphate backbones are relatively far apart. This space...
Cellular Injury V: Apoptosis and Autophagy01:22

Cellular Injury V: Apoptosis and Autophagy

Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...