AI Article Synopsis
- CXCR3 is a G protein-coupled receptor that changes shape when it binds to a ligand, sending signals into cells.
- The researchers used molecular-dynamics simulations to explore the binding sites of two compounds: FAUC1036 (an agonist) and RAMX3 (a negative modulator).
- They discovered two separate binding pockets on CXCR3: a shallow site for FAUC1036 and a deeper site for RAMX3, supporting their hypothesis that these compounds act via different mechanisms.
Article Abstract
The chemokine receptor CXCR3 is a G protein-coupled receptor that conveys extracellular signals into cells by changing its conformation upon ligand binding. We previously hypothesized that small-molecule allosteric CXCR3-agonists do not bind to the same allosteric binding pocket as 8-azaquinazolinone-based negative allosteric modulators. We have now performed molecular-dynamics (MD) simulations with metadynamics enhanced sampling on the CXCR3 system to refine structures and binding modes and to predict the CXCR3-binding affinities of the biased allosteric agonist FAUC1036 and the negative allosteric modulator RAMX3. We have identified two distinct binding sites; a "shallow" and a second "deeper" pocket to which the biased allosteric agonist FAUC1036 and negative allosteric modulator RAMX3 bind, respectively.
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| http://dx.doi.org/10.1002/anie.201607831 | DOI Listing |
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