APS March Meeting 2014
Volume 59, Number 1
Monday–Friday, March 3–7, 2014;
Denver, Colorado
Session T12: Invited Session: Functional Dynamics of Proteins from Physics to Biology
11:15 AM–2:15 PM,
Thursday, March 6, 2014
Room: 205
Sponsoring
Unit:
DBIO
Chair: Xiang-Qiang Chu, Wayne State University, and Michael Brown, University of Arizona
Abstract ID: BAPS.2014.MAR.T12.4
Abstract: T12.00004 : Conformational Fluctuations in G-Protein-Coupled Receptors
1:03 PM–1:39 PM
Preview Abstract
Abstract
Author:
Michael F. Brown
(University of Arizona)
G-protein\textbf{-}coupled receptors (GPCRs) comprise almost 50{\%} of
pharmaceutical drug targets, where rhodopsin is an important prototype and
occurs naturally in a lipid membrane. Rhodopsin photoactivation entails
11-\textit{cis} to all-\textit{trans} isomerization of the retinal cofactor, yielding an equilibrium
between inactive Meta-I and active Meta-II states. Two important questions
are: (1) Is rhodopsin is a simple two-state switch? Or (2) does
isomerization of retinal unlock an activated conformational ensemble? For an
ensemble-based activation mechanism (EAM) [1] a role for conformational
fluctuations is clearly indicated. Solid-state NMR data together with
theoretical molecular dynamics (MD) simulations detect increased local
mobility of retinal after light activation [2]. Resultant changes in local
dynamics of the cofactor initiate large-scale fluctuations of transmembrane
helices that expose recognition sites for the signal-transducing G-protein.
Time-resolved FTIR studies and electronic spectroscopy further show the
conformational ensemble is strongly biased by the membrane lipid
composition, as well as pH and osmotic pressure [3]. A new flexible surface
model (FSM) describes how the curvature stress field of the membrane governs
the energetics of active rhodopsin, due to the spontaneous monolayer
curvature of the lipids [4]. Furthermore, influences of osmotic pressure
dictate that a large number of bulk water molecules are implicated in
rhodopsin activation. Around 60 bulk water molecules activate rhodopsin,
which is much larger than the number of structural waters seen in X-ray
crystallography, or inferred from studies of bulk hydrostatic pressure.
Conformational selection and promoting vibrational motions of rhodopsin lead
to activation of the G-protein (transducin). Our biophysical data give a
paradigm shift in understanding GPCR activation. The new view is: dynamics
and conformational fluctuations involve an ensemble of substates that
activate the cognate G-protein in the amplified visual response.\\[4pt]
[1] A. V. Struts et al. (2011) \textit{Nat. Struct. Mol. Biol.} \textbf{18}, 392.\\[0pt]
[2] A. V. Struts et al. (2011)~\textit{PNAS}$~$\textbf{108}, 8263.\\[0pt]
[3] M. Mahalingam et al. (2008) \textit{PNAS} \textbf{105}, 17795.\\[0pt]
[4] M. F. Brown (2012) \textit{Biochemistry} \textbf{51}, 9782.
To cite this abstract, use the following reference: http://meetings.aps.org/link/BAPS.2014.MAR.T12.4