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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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Allosteric Proteins-ATCase01:19

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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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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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Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
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Ligand Binding and Linkage00:49

Ligand Binding and Linkage

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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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Exploring Caspase Mutations and Post-Translational Modification by Molecular Modeling Approaches
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Tailoring small molecules for an allosteric site on procaspase-6.

Jeremy Murray1, Anthony M Giannetti, Micah Steffek

  • 1Departments of Structural Biology, Biochemical Pharmacology, Neuroscience, and Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 (USA). murray.jeremy@gene.com.

Chemmedchem
|November 22, 2013
PubMed
Summary

Researchers identified small molecules that allosterically inhibit caspase-6, a target in neurodegenerative diseases. This fragment-based approach stabilizes the procaspase-6 zymogen, offering a new therapeutic strategy.

Keywords:
caspase modulationcaspase-6drug designfragment mergingfragment screening

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Area of Science:

  • Biochemistry
  • Drug Discovery
  • Neuroscience

Background:

  • Caspases are key regulators of apoptosis and implicated in neurodegenerative diseases.
  • Developing active-site inhibitors for caspases has been challenging.
  • Allosteric modulation offers an alternative therapeutic strategy for targeting caspases.

Purpose of the Study:

  • To discover allosteric inhibitors of caspase-6 using a fragment-based approach.
  • To identify small molecules that modulate caspase-6 activity.
  • To explore therapeutic strategies for neurodegenerative diseases involving caspase-6.

Main Methods:

  • Fragment-based lead discovery using surface plasmon resonance (SPR).
  • X-ray crystallography to determine fragment binding sites.
  • Fragment merging to develop high-affinity ligands.
  • Biochemical assays to assess caspase-6 activity and stabilization.

Main Results:

  • Identified fragments binding to a putative allosteric site at the procaspase-6 dimer interface.
  • Determined crystal structures revealing fragment interactions with the L2 loop.
  • Developed nanomolar-affinity ligands through fragment merging.
  • Demonstrated stabilization of procaspase-6 by the identified ligands.

Conclusions:

  • A fragment-based strategy successfully identified allosteric inhibitors of caspase-6.
  • The identified ligands stabilize procaspase-6 by targeting the L2 loop at the dimer interface.
  • This approach offers a promising strategy for developing drug-like small molecules for allosteric control of caspase-6 activation.