O'BRIEN
LAB
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O’Brien Lab

My lab focuses on understanding and exploiting the complex signaling properties of human membrane proteins with a particular focus on G-protein coupled receptors (GPCRs). GPCRs adopt a very broad set of distinct conformations, the populations and dynamics of which are highly important for determining their diverse signaling outcomes. It is because of their complex signaling profiles as well as their involvement in nearly all areas of human physiology that GPCRs are the targets for >1/3 of all FDA approved drugs. We use cryo-electron microscopy in conjunction with various protein dynamics techniques (principally solution nuclear magnetic resonance (NMR)) to understand at the atomic level how receptor thermodynamics drives activity. To facilitate these studies, we are developing cryoEM and NMR methods suited for detailed characterizations of fleeting yet highly important GPCR intermediate states. In order to exploit our novel mechanistic insights into GPCR signaling, the lab develops new DNA-encoded library (DEL) screening approaches for use in small molecule discovery programs in conjunction with leading academic and industry collaborators. In short, we do GPCR biophysics with an eye towards the clinic!

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Featured Publications

Rangari VA*, O’Brien ES*, Powers AS*, Slivicki RA*, Bertels Z*, Appourchaux K, Aydin D, Ramos-Gonzalez N, Mwirigi J, Lin L, Mangutov E, Sobecks BL, Awad-Agbaria Y, Uphade MB, Aguilar J, Peddada TN, Shiimura Y, Huang XP, Folarin-Hines J, Payne M, Kalathil A, Varga BR, Kobilka BK, Pradhan AA, Cameron MD, Krishna Kumar K, Dror RO, Gereau IV RW, Majumdar S. A cryptic pocket in CB1 drives peripheral and functional selectivity. Nature. 2025; 640: 265-273.

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.

Zhao J, Elgeti M, O’Brien ES, Sar C, El Daibani A, Heng J, Sun X, Che T, Hubbell W, Kobilka BK, Chen C. Ligand efficacy modulates conformational dynamics of the µ-opioid receptor. Nature. 2024; 629: 474-480.

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.