Department of Physiology & Membrane Biology
School of Medicine, University of California
Master of Science (M.S.) Degree in Physics, Department of Physics, Moscow State University, Moscow, Russia.
Doctor of Philosophy (Ph.D.) Degree in Biochemistry and Molecular Biology, Department of Environmental and Biomolecular Systems, OGI School of Science & Engineering, Oregon Health Science University, Portland, Oregon.
Senior Fellow in Computational Biology and Biophysics. Supervisors: Dr. David Baker, Professor, Department of Biochemistry, and Dr. William A. Catterall, Professor and Chairman, Department of Pharmacology, University of Washington, Seattle, Washington.
Assistant Professor, Department of Physiology and Membrane Biology, University of California, Davis, CA
Associate Professor, Department of Physiology and Membrane Biology, University of California, Davis, CA
Professor, Department of Physiology and Membrane Biology, University of California, Davis, CA
Member of the American Pain Society
Member of the Biophysical Society
My research interests and expertise encompass neuroscience, protein structure, computational biology, and evolution. Main focus of my research group is on structure and function studies of voltage-gated ion channels, computational design and chemical synthesis of subtype-specific modulators of voltage-gated ion channels, development of computational methods for membrane protein structure prediction and design, and analysis of evolution of human voltage-gated ion channels. Function and modulation of neuronal sodium channels are critical for the neuromodulation of electrical excitability and synaptic transmission in neurons - the basis for many aspects of signal transduction, learning, memory and physiological regulation. Mutations in neuronal voltage-gated sodium channel genes are responsible for various human neurological disorders. Furthermore, human neuronal voltage-gated sodium channels are primary targets of therapeutic drugs used as local anesthetics and for treatment of neurological and cardiac disorders. My first project is focusing on studying of neuronal voltage-gated sodium channels structure, function, and modulation in order to design new therapeutically useful drugs for treatment of pain and epilepsy. Serious, chronic pain affects at least 116 million Americans each year and epilepsy affects nearly 3 million Americans and 50 million people Worldwide. However, the treatment of chronic pain and epilepsy remains a major unmet medical need because the use of currently available drugs is limited due to incomplete efficacy and/or significant side effects. Considerable efforts by pharmaceutical industry toward identifying selective inhibitors of one or more of Nav channel subtypes did not generate any genuinely subtype selective blockers and none are currently advancing through clinical trials. My laboratory uses an innovative approach to design novel subtype selective Nav channel blocking drugs with high efficacy and minimum side effects. Novel drugs will be tested using methods of electrophysiology, biochemistry, and molecular biology. This project will provide key structural information on the molecular basis of neuronal voltage-gated sodium channels function and its interaction with therapeutically useful subtype-specific modulators. Understanding of function and modulation of the neuronal voltage-gated sodium channels on structural level will give us profound insights into the fundamental mechanisms underlying neuromodulation and signal transduction.
Over the past decade, there has been significant progress in determining membrane protein structures in general and ion channel structures in particular using x-ray crystallography methods. However, it is still very difficult to obtain high-resolution structural information about these proteins. My second project is focusing on further development of the Rosetta-Membrane computational method for high-resolution membrane protein structure prediction and design. I developed the original Rosetta-Membrane method for membrane protein structure prediction in collaboration with David Baker's group at the University of Washington and applied it for modeling of membrane proteins in general and ion channels in particular. I now propose to further improve accuracy of the Rosetta-Membrane method and expand its capabilities to design membrane proteins with new functions.
Evolution of ion channels from bacteria to human took several billion years and while there are basic features that are common to bacterial and human ion channels, such as pore-forming and/or voltage-sensing domains, there are abundance of unique features in every human ion channel family that are absent in bacterial ion channels and have been designed through evolutionary time to accomplish highly specific functions. My third project is focusing on exploring evolution of human voltage-gated ion channels using available prokaryotic and eukaryotic genomes and high-resolution ion channels structures. Human ion channel family is ranking third in a number of family members after the G protein coupled receptors and the protein kinases. To identify the mechanisms by which historical mutations generated distinct human ion channel functions, it is essential to compare proteins through evolutionary time. Moreover, reconstruction of key intermediate ancestors of ion channels by computational structural design can further advance our understanding of evolution of human ion channel function. Previously, I used bioinformatics based analysis of available high-resolution membrane proteins structures to derive parameters of membrane environment-specific scoring function used in the Rosetta-Membrane method. I now propose to analyze evolution of human voltage-gated sodium channels using phylogenetic trees and multiple sequence alignments of homologous sequences and correlate it with available structural and functional data. I will use the Rosetta-Membrane method to predict structures of human ion channels for which high-resolution structures are not available. Mapping of evolutionary information onto human voltage-gated sodium channel structures will give us significant new insights into evolution of their structure and function.
Department of Anesthesiology and Pain Medicine: Scott Fishman
Department of Biochemistry and Molecular Medicine: Kit Lam, Justin Siegel, Lin Tian, and John Voss
Department of Biomedical Engineering: Marc Facciotti
Department of Cell Biology and Human Anatomy: Paul Fitzgerald
Department of Internal Medicine: Nipavan Chiamvimonvat
Department of Molecular and Cellular Biology: Jonathan Scholey
Department of Neurobiology, Physiology and Behavior: James Trimmer
Department of Pharmacology: Donald Bers, Colleen Clancy, Elva Diaz, and Heike Wulff
Department of Physiology and Membrane Biology: Pete Cala, Michel Ferns, Alla Fomina, Jon Sack, and Jie Zheng
City College of New York: Themis Lazaridis
Johns Hopkins University: Mark Donowitz and Jeff Gray
National Institutes of Health: Kenton Swartz
Royal Melbourne Institute of Technology (Australia): Toby Allen
Stanford University: Justin Du Bois
University of Calgary (Canada): Sergei Noskov
University of California Berkeley: Ehud Isacoff
University of California San Francisco: Bill DeGrado and Daniel Minor
University of Chicago: Benoit Roux
University of Copenhagen (Denmark): Stine Pedersen
University of Innsbruck (Austria): Bernhard Flucher and Joerg Striessnig
University of Utah: Baldomero Olivera
University of Washington: David Baker, William Catterall, and Allan Rettie
Vanderbilt University: Jens Meiler
Weizmann Institute of Science (Israel): Sarel Fleishman
Interactive 3D environment: