Kobilka, Brian K.
Most widely held works by Brian K Kobilka
NMR spectroscopy for structural and dynamic studies of the beta2-adrenergic receptor by Michael Paul Bokoch ( Book )
1 edition published in 2010 in English and held by 2 libraries worldwide
G protein coupled receptors (GPCRs) are seven transmembrane proteins that are expressed in all eukaryotic cells and tissues. These receptors play key roles in human physiology and disease. The goal of my work is to understand the molecular detail of ligand recognition by GPCRs, and how this process leads to conformational changes that manifest as cellular signaling. Meeting this goal will advance our knowledge of membrane protein biology. It will also reveal structural targets and physicochemical logic to aid pharmaceutical design. The age of GPCR structural biology recently arrived with the first x-ray structures of rhodopsin and the beta2 adrenergic receptor (beta2AR). However, membrane proteins are constantly fluctuating entities. Dynamic behavior is intrinsic to their function. As such, static x-ray structures alone are inadequate. Herein, I develop biophysical techniques to study these dynamic receptors. Using NMR spectroscopy, I characterize conformational changes in the extracellular region of the beta2AR, a surface rich with potential for drug design. I also explore the signaling properties of monomeric GPCRs and conformational changes of other macromolecules using single-molecule fluorescence. While many questions about GPCRs remain, I hope this work is a small step towards understanding these important, fascinating, and beautiful molecules.
Optical techniques for integrated control and recording of neural activity by Raag Dar Airan ( Book )
1 edition published in 2010 in English and held by 1 library worldwide
A long-standing objective of psychiatry has been the ability to both control and record the activity of precisely-defined populations of brain cells on the millisecond timescale most relevant for neural computation. Recent advances bring that goal increasingly near by leveraging the genetically-precise techniques of molecular biology with the high-speed, multiplexed command afforded by optical technologies to introduce and utilize light-sensitive neural activity control integrated with fast neural circuit imaging. In this thesis, I present exemplars of these technological advances and demonstrate their utility in illuminating the neural circuit basis of behaviors relevant to understanding psychiatric disease. I first show how fast neural circuit imaging may be integrated with optical neural control tools to develop insight into the role of genetically, developmentally, or projection defined populations of brain cells in mediating circuit-level physiological changes. I then demonstrate computational methods to analyze the resultant imaging data and apply fast circuit imaging to delineate links between hippocampal physiology and behavior in an animal model of depression. Finally, I present the development of a novel class of optically-activated, genetically-targetable control tools that permit optical control of G-protein coupled intracellular signaling; and the use of these molecular devices to determine causal roles of neuromodulatory inputs in reward processing. The development of these and similar optical modalities further improves the precision of questions addressable by the neuroscientist, and potentially the extent of disease treatable by the clinician.