Jacob P Mahoney
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Research Subjects
Jacob P Mahoney has a total of 4 co-authors. Here are the top co-authors by number of shared publications:
- Aashish Manglik
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, United States
1 shared publication - John R. Traynor
Department of Pharmacology, Edward F. Domino Research Center, Medical School, University of Michigan, Ann Arbor, Michigan; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan
1 shared publication - Kathryn E. Livingston
Department of Pharmacology and Edward F Domino Research Center, University of Michigan Medical School, Ann Arbor, Michigan (I.J.D., R.C., A.M.S., K.E.L., J.R.T., E.M.J.); Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom (A.D., S.M.H.); and Drug Design and Synthesis Section, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland (K.C.R.)
1 shared publication Roger K Sunahara
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, United States
1 shared publication
Latest Publications
- Open Access
- 22 June 2018
- Published by eLife Sciences Publications, Ltd in eLife
- Vol. 7
Measuring ligand efficacy at the mu-opioid receptor using a conformational biosensor
The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (µ-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to µ-OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of µ-OR. We further show that positive allosteric modulators of µ-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell-free, signal transduction-independent and is generally applicable to GPCRs.
- 22 June 2018
- Published by eLife Sciences Publications, Ltd in eLife
- Vol. 7
Open AccessMeasuring ligand efficacy at the mu-opioid receptor using a conformational biosensor
The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (µ-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to µ-OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of µ-OR. We further show that positive allosteric modulators of µ-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell-free, signal transduction-independent and is generally applicable to GPCRs.