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Related Concept Videos

Caspases01:24

Caspases

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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...
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The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

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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...
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The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

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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...
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Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

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Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
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cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

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Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
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Apoptosis01:30

Apoptosis

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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...
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Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches
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Modulating caspase activity: beyond the active site.

Jeremy Murray1, Adam R Renslo

  • 1Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.

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Summary
This summary is machine-generated.

Targeting caspases (proteases regulating apoptosis and inflammation) offers therapeutic potential. New research reveals novel allosteric small molecule modulators that bind distant sites, impacting caspase activity and opening new therapeutic avenues.

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Area of Science:

  • Biochemistry
  • Biophysics
  • Pharmacology

Background:

  • Caspases are critical cysteine proteases regulating apoptosis and inflammation.
  • Despite therapeutic interest for diseases like cancer, active-site directed small molecules have failed in clinical trials.
  • Caspases exhibit dynamic activation mechanisms and possess allosteric sites.

Purpose of the Study:

  • To explore novel strategies for modulating caspase activity.
  • To investigate the potential of allosteric small molecules for therapeutic intervention.
  • To highlight recent advancements in understanding caspase regulation.

Main Methods:

  • Biochemical and biophysical studies of caspase dynamics and activation.
  • Identification and characterization of small molecules targeting allosteric sites.
  • Analysis of novel caspase modulation mechanisms, including substrate complex binding and tetramer stabilization.

Main Results:

  • Small molecules binding to allosteric sites modulate caspase catalytic activity by altering active site structure.
  • Both cysteine-tethered and non-covalent reversible molecules targeting allosteric sites have been identified.
  • New modulators include a molecule binding caspase-6-substrate complexes and a peptide stabilizing inactive procaspase-6.

Conclusions:

  • Allosteric modulation offers a promising alternative to active-site-directed inhibition for targeting caspases.
  • Recent discoveries provide exciting new avenues for developing caspase-modulating therapeutics.
  • Understanding caspase dynamics and allosteric regulation is key for future drug development.