Our lab uses a combination of computational and experimental approaches to try to understand the atomic and molecular details governing the function of protein complexes involved in intercellular communication. The complexes that are studied include ionotropic glutamate receptors (iGluRs). iGluRs are ligand-gated ion channels that mediate the majority of excitatory synaptic transmission in the central nervous system. iGluRs are important in synaptic plasticity, which underlies learning and memory. Receptor dysfunction has been implicated in a number of neurological disorders. The binding of neurotransmitter molecules to the ligand-binding domains of iGluRs drives the opening of the associated transmembrane pore, allowing cations to flow into the cell, which in turn triggers a nerve impulse.
Computationally, we apply methods in molecular simulation and statistical thermodynamics to estimate the free energies and kinetics associated with ligand binding and protein conformational transitions. Our goal is to generate testable predictions that can help guide experimental investigations as well as help interpret experimental observations. Computational protein design is also explored. Experimentally, we pursue structural studies primarily using X-ray crystallography to help characterize macromolecular structure-function relationships. Biophysical insights can collectively be applied to the design of therapeutic agents.
Yao Y., Belcher J., Berger A.J., Mayer M.L., and Lau A.Y. Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics. Structure, in press, 2013.
Lau A.Y., Salazar H., Blachowicz L., Ghisi V., Plested A.J.R., and Roux B. A conformational intermediate in glutamate receptor activation. Neuron, in press, 2013.
Lau A.Y. and Roux B. The hidden energetics of ligand binding and activation in a glutamate receptor.Nat. Struct. Mol. Biol.,18, 283-287, 2011.
Contreras J.E., Chen J., Lau A.Y., Jogini V., Roux B., and Holmgren M. Voltage profile along the permeation pathway of an open channel. Biophys. J.99, 2863-2869, 2010.
Kollewe A., Lau A.Y., Sullivan A., Roux B., and Goldstein S.A.N. A structural model for K2P potassium channels based on 23 pairs of interacting sites and continuum electrostatics. J. Gen. Physiol.134, 53-68, 2009.
Numano R., Szobota S., Lau A.Y., Gorostiza P., Volgraf M., Roux B., Trauner D., and Isacoff E.Y. Nanosculpting reversed wavelength sensitivity into a photoswitchable iGluR. Proc. Natl. Acad. Sci.USA 106, 6814-6819, 2009.
Lau A.Y. and Roux B. The free energy landscapes governing conformational changes in a glutamate receptor ligand-binding domain. Structure 15, 1203-1214, 2007.
Lau A.Y. and Chasman D.I. Functional classification of proteins and protein variants. Proc. Natl. Acad. Sci.USA 101,6576-6581, 2004.
Lau A.Y., Wyatt M.D., Glassner B.J., Samson L.D., and Ellenberger T.E. Molecular basis for discriminating between normal and damaged bases by the human alkyladenine glycoslase, AAG. Proc. Natl. Acad. Sci. USA 97, 13573-13578, 2000.
Lau A.Y., Schärer O.D., Samson L., Verdine G.L., and Ellenberger T. Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA: mechanisms for nucleotide-flipping and base excision. Cell 95, 249-258, 1998.