Assay Development and Protein Purification News from Cytoskeleton's Lab

 

Tubulin Polymerization Inhibitor Screening

Microtubules (MTs) are comprised of α/β tubulin heterodimers which have polymerized into cylinderical structures. MTs serve as an essential component of a cell’s cytoskeleton as they regulate and participate in a variety of cellular functions that include motility, morphology, intracellular transport, signal transduction, and cell division (Fig. 1). The cell cycle consists of the sequential G1, S, G2, and M phases with MT polymerization and depolymerization (i.e., MT dynamics) playing a key role in the normal progression of this cycle to insure proper cell division (Fig. 1). The disruption of MT dynamics, and thereby the cell cycle, leads to cell death. As such, MTs are a well-recognized and often-studied target for cancer drug discovery efforts1-4...

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KSP/Eg5 Inhibition in Parasites and Fungi

The Kinesin Spindle Protein (KSP; a.k.a. Eg5 or KIF11) is a plus end-directed Kinesin-5 (a.k.a. BimC) subfamily member and has been the focus of significant drug development efforts for decades.  Currently, KSP (or its homologs) is a target for anti-mitotics (cancer)1,2, anti-parasitics (malaria)3, and anti-fungals4. As a microtubule (MT) cross-linking enzyme, KSP plays a critical role in mitotic spindle pole separation, and its inhibition results in the formation of monoaster spindles which is thought to lead to mitotic catastrophe and apoptosis (Fig. 1). The targeting of KSP as a treatment for cancer is well-documented1,2,5,6. The purpose of this newsletter is to briefly discuss KSP homologs as a therapeutic target for parasitic and fungal diseases...

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Drugable Site Selection for KSP Inhibitors

Since the discovery of the first kinesin spindle protein (KSP, also known as Eg5, KIF11) inhibitor, monastrol, in 1999 (1), there have been a plethora of articles, 3D structures, and FDA applications based on the same binding site (review [2]). The binding site is called the allosteric monastrol binding site (AMBS) which functionally plays a significant role in transducing chemical energy to movement of the neck-linker region. Drugs that bind this site are non-competitive...

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KSP/Eg5 Inhibition in Cancer: Theory and Therapy

The Kinesin Spindle Protein (KSP; also known as Eg5 or KIF11) is a Kinesin-5 subfamily member and has been the focus of a significant drug development effort throughout the pharmaceutical industry for the last 15 years. KSP plays a critical role in mitotic spindle pole separation, and its inhibition results in the formation of monoaster spindles which is thought to lead to mitotic catastrophe and apoptosis1. From a therapeutic standpoint...

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Compound Screening, Protein Purification, & Assay Development

As Cytoskeleton’s Custom Services Department continues to grow and expand its offerings, we wanted to take the opportunity to highlight some past research projects that benefited from work performed by Cytoskeleton’s Custom Services scientists.  The three main foci of Cytoskeleton’s Custom Services are: 1) Compound Screening, 2) Assay Development, and 3) Gene Cloning and Recombinant/Native Protein Purification.  The citations discussed below demonstrate our effectiveness in all three types of custom services...

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KIF7 Kinesin Motor Assay

KIF7 is a Kinesin-4 family member that has been shown to play an important role in embryonic development and may play a role in the development of basal cell carcinomas. KIF7 functions in Hedgehog (Hh) signaling through the negative and positive regulation of the GLI family of transcription factors (i.e., GLI1, GLI2, and GLI3)1.  While the mechanism of this regulation is still being elucidated, it appears that in the absence of an Hh ligand, KIF7 negatively regulates GLI transcription factor activity, and in the presence of Hh signaling it positively influences GLI dependent signaling; possibly through KIF7’s Hh-dependent translocation from the base of primary cilia to the tip1.  Mice lacking KIF7 exhibit a ...

Read more about KIF7 Kinesin Motor Assay Here.

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