Mechanisms of Information Transfer across Biological …rnc.rpi.edu/2014Symposium/Neale, Christopher...

Mechanisms of Information Transfer across Biological Membranes: G protein-Coupled Receptors

Chris Neale

Postdoc

Department of Physics, Applied Physics, and Astronomy

Rensselaer Polytechnic Institute, Troy, NY, USARensselaer Polytechnic Institute, Troy, NY, USA

2014 Rensselaer Nanotechnology Center Research SymposiumWednesday, October 29, 2014

Advisor: Angel E. García

Collaborators: Régis Pomès, University of Toronto, Canada

Creative Commons (Asd.and.Rizzo)

Creative Commons (Mariana Ruiz)

Cell membranes

M.W. Brightman and T.S. Reese. J. Cell. Biol. 1969. 40(3):648-77

x34,000

Membrane proteins

GPCRs are excellent drug targets

Information

InformationA.L. Hopkins, C.R. Groom. Nat. Rev. Drug Discov. 2002. 1(9):727-730

GPCR activation

PDB: 3SN6; Rasmussen et al. Nature. 2011. 477:549-555

An “ionic lock” stabilizes inactive conformations

inactiveactive inactiveactive

Molecular dynamics simulations

Spontaneous formation of the ionic lock

The cytosolic binding pocket is more stable in apo-state simulations using a crystal structure containing a G protein than a mimetic nanobody

The ionic lock forms less frequently in apo-state simulations using a crystal structure containing a G protein than a mimetic nanobody

What is the molecular source of this differential active-state stability?

Future work

Supervisor:Dr. Angel García

Group Members:Anthony BishopCalvin ChenDr. Charles EnglishDr. Henry HerceJoel JankeRyan KrafnickBryan MakowskiTyler MasonJacob MinerDavid RosenmanJorge OchoaJorge Ochoa

Recent Alumni:Dr. Alan ChenDr. Camilo Jimenez-CruzDr. Kun HuangDr. Akansha Saxena

MCB-1050966