Evan O’Brien
725 N. Wolfe Street
WBSB 708
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 screening approaches to be used in small molecule discovery programs in conjunction with leading academic and industry collaborators.
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.
Hilger D, Krishna Kumar K, Hu H, Pedersen MF, O’Brien ES, Giehm L, Jennings C, Eskici G, Inoue A, Lerch M, Mathiesen JM, Skiniotis G, Kobilka BK. Structural insights into differences in G protein activation by family A and family B GPCRs. Science. 2020; 369(6503): eaba 3373.
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, Lin DW, Fuglestad B, Stetz MA, Gosse T, Tommos C, Wand AJ. Improving yields of deuterated, methyl labeled protein by growing in H2O. J Biomol NMR. 2018; 71(4): 263-273.
O’Brien ES, Sharp KA, Wand AJ. On the ability of molecular dynamics force fields to recapitulate NMR derived protein side chain order parameters. Prot Sci. 2016; 25(6): 1156-60.
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.