Conformational Change
Definition:
An alteration of the shape of a protein due to different factors such as pH, temperature, or binding of a molecule.
Image: An allosteric inhibitor binds to a separate area from the active site called an allosteric site. After binding, the inhibitor will change the shape of the active site, a conformational change, preventing the substrate from binding.
Relevance:
The shape or structure of a protein determines its function; therefore, conformational changes can cause activation or deactivation of the protein, influence binding, and initiate or terminate signalling cascades. For example, in non-competitive inhibition, the binding of the inhibitor to an allosteric site causes a conformational change in the enzyme or receptor. Thus, the active site is affected and loses affinity for the substrate, causing a decrease in the activity of the enzyme; or a receptor loses affinity for its ligand.
Example:
A group of proteins that undergo conformational changes to become activated are protein kinases (PKs), which are necessary for signal transduction in many processes. For example, mitogen-activated protein kinases (MAPKs) are phosphorylated at certain regions, leading to conformational changes in the protein, initiating its activation. This signal transduction pathway is often a target for cancer chemotherapy due to the constant activation of these enzymes in many malignancies.
Teaching Tips:
https://www.youtube.com/watch?v=d_etkljNZxk
Linked terms: Ligand, Substrate, Transmembrane receptor, Enzyme, Non-competitive inhibition, Allosteric site
Resources:
Deodhar, M., Al Rihani, S. B., Arwood, M. J., Darakjian, L., Dow, P., Turgeon, J., & Michaud, V. (2020). Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice. Pharmaceutics, 12(9), 846. https://doi.org/10.3390/pharmaceutics12090846
Lewis, T. (2023, April 24). Biochemistry, Proteins Enzymes. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK554481/
Lopez, E. D., Burastero, O., Arcon, J. P., Defelipe, L. A., Ahn, N. G., Marti, M. A., & Turjanski, A. G. (2020). Kinase Activation by Small Conformational Changes. Journal of chemical information and modeling, 60(2), 821–832. https://doi.org/10.1021/acs.jcim.9b00782
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