Evan O'Brien

My lab is interested in studying G-protein coupled receptor (GPCR) structure & dynamics, with an eye towards developing next-gen therapeutics targeting this complex set of receptors. These proteins are pivotal drug targets with extremely complex signaling behaviors. This complexity is driven by the wide array of conformations they can adopt within the membrane. To better understand this conformational landscape, we combine high-resolution structural biology (cryoEM) with solution dynamics techniques (NMR) to generate atomic-resolved “movies” of receptors in action. Past mechanistic insights into allostery within these proteins, we aim to discover drugs that can better exploit this complex signaling behavior in a more targeted manner to increase efficacy and decrease side effects. Our systems are varied, but mostly focus on problems in neuroscience, maternal health, and cardiovascular health.

Selected Publications:

O’Brien ES, Rangari VA, El Daibani A, Eans SO, Hammond HR, White E, Wang H, Shiimura Y, Krishna Kumar K, Jiang Q, Appourchaux K, Huang W, Zhang C, Kennedy BJ, Mathiesen JM, Che T, McLaughlin JP, Majumdar S, Kobilka BK. A µ-opioid receptor modulator that works cooperatively with naloxone. Nature. 2024; 631: 686-693.

Krishna Kumar K,* O’Brien ES*, Habrian C, Latorraca NR, Wang H, Tuneew I, Montabana E, Marqusee S, Hilger D, Isacoff EY, Mathiesen JM, Kobilka BK. Negative allosteric modulation of the glucagon receptor by RAMP2. Cell. 2023; 186(7): 1465-77. *Co-first authors

O’Brien ES, Fuglestad B, Lessen HJ, Stetz MA, Lin DW, Marques BS, Fleming KG, Wand AJ. Membrane proteins have distinct fast internal motion and residual conformational entropy. Angew Chemie Int Ed. 2020; 59(27): 11108-11114.

O’Brien ES, Nucci NV, Fuglestad B, Tommos C, Wand AJ. Defining the apoptotic trigger: the interaction of cytochrome c and cardiolipin. J Biol Chem. 2015; 290(52): 30879-87.