Small molecules, such as drugs, interact with membrane proteins directly and will also modify the lipid bilayer. This concept can be exploited to give valuable insight into the cytotoxicity of vast libraries of compounds. Here’s an opportunity to attend a two-part series of live webinars discussing the concept of bilayer modification by small molecules and how you can utilise it to characterise the potency of potential toxins. The two 30-minute sessions will include time for questions on the regulation of membrane protein function. Register now!
Webinar Title: Bilayer-Mediated Regulation of Membrane Protein Function by Small Molecules
Learn more about using single-mixing stopped-flow spectrofluorometry to quantify the bilayer-modifying potency of bioactive molecules.
Membrane proteins are coupled to their host lipid bilayer through hydrophobic interactions that minimise the exposure of hydrophobic surfaces to water. Consequently, membrane protein conformational changes that involve the bilayer-spanning domains will alter the lipid organisation adjacent to the protein. This lipid reorganisation has an associated energetic cost, which becomes the bilayer contribution to the energy change associated with the conformational transition. The bilayer contribution varies as a function of the host bilayer’s material properties (thickness, intrinsic curvature, and the associated elastic moduli); membrane proteins’ conformational preference thus will vary with changes in bilayer elastic properties. Amphiphiles, including many biologically active compounds, are potent modifiers of bilayer elasticity meaning that the energetic coupling between membrane proteins and their host bilayer provides for a mechanism by which amphiphilic drugs regulate membrane protein function without direct binding to the proteins in question.
This webinar will focus on: first, the basics of bilayer-mediated regulation of membrane protein function; and second, how to quantify the bilayer-modifying potency of amphiphiles using single-mixing stopped-flow spectrofluorometry.
Date: 18th March 2021
Time: 11:00 EDT | 15:00 GMT
Presented by: Olaf S. Andersen, M.D.
Professor of Physiology and Biophysics
Weill Cornell Medical College
Registration Link: https://attendee.gotowebinar.com/register/1249336992395067406?source=Website
Webinar Title: Mechanisms underlying drug-mediated regulation of membrane proteins: Using sequential mixing stopped-flow to study the regulation of membrane protein function
Membrane proteins are key targets in the pharmacological regulation of cell function. Underlying mechanisms governing drug downstream effects are often not clearly understood as off-target effects of many drugs involve the regulation of multiple membrane proteins. The plurality of protein targets that a drug can affect at the same concentration suggests a common, non-specific, mechanism. Membrane proteins are tightly coupled to the host lipid bilayer, therefore, changes in lipid bilayer properties (i.e. thickness, curvature, elasticity) regulate protein function. Most drugs are amphiphiles, being able to partition into and alter lipid bilayer properties. We study the role of drug-mediated changes in bilayer properties in their effects on membrane proteins.
In this webinar, we present our results showing regulation of a prototypical ion channel, KcsA, first by changes in bilayer thickness and second by a set of drugs that vary in their bilayer modifying potency as sensed by gramicidin channels.
Using sequential-mixing stopped-flow spectrofluorometry we interrogate different gating steps of KcsA in the presence of drugs in different bilayer environments, to show that drugs indeed can regulate membrane protein function via the bilayer. Finally, we present tools and strategies for parsing out whether mechanisms for the observed drug effects are mediated by the lipid bilayer or direct drug-protein interactions.
Date: 8th April 2021
Time: 11:00 EDT | 16:00 BST
Presented by: Radda Rusinova, Ph.D.
Assistant Professor of Research in Physiology and Biophysics
Department of Physiology and Biophysics
Weill Cornell Medicine
Registration Link: https://attendee.gotowebinar.com/register/4422461579459151374?source=website
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