2016 Poster Sessions : Computational Studies of a Constitutively Active G Protein-coupled Receptor

Student Name : Naomi Latorraca
Advisor : Ron Dror
Research Areas: Artificial Intelligence
Constitutive activity—the ability to signal to a downstream binding partner in the absence of a bound drug or hormone—varies widely across the set of all GPCRs, which make up the largest family of membrane proteins and largest family of drug targets. Constitutive activity is particularly characteristic of viral GPCRs, where it can enhance virulence. Recently, two crystal structures of the human cytomegalovirus chemokine receptor US28 were solved in an active-like signaling state in complex with a protein ligand. Although related chemokine receptors have been crystallized previously, US28 is unique in that it demonstrates high levels of constitutive activity. We therefore sought to better understand the structural basis for constitutive activity at US28 using a combination of sequence-structure analysis and molecular dynamics (MD) simulation. We identified a network of residues unique to US28 that appear to destabilize the inactive state relative to other related GPCRs (Burg et al., Science 2015). Contacts among several other residues in this neighborhood differ between US28 and related chemokine receptors as well, and we are currently pursuing MD simulations to ask whether mutants that resemble non-US28 chemokine receptors work to destabilize the US28 active state. Taken together, these data suggest that differences in interaction networks in both the active and inactive states across GPCRs appear to regulate levels of receptor constitutive activity.

Naomi Latorraca is a 3rd year biophysics Ph.D. student in Ron Dror’s lab, where she uses biomolecular simulations to understand the dynamic behavior of membrane proteins as they interact with molecules in their surrounding environment.