研究领域
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.
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Tuluc P*, Yarov-Yarovoy V*, Benedetti B, Flucher BE (2016) Molecular Interactions in the Voltage Sensor Controlling Gating Properties of Cav Calcium Channels. Structure 24, 261-71.
Yang F, Vu S, Yarov-Yarovoy V, Zheng J (2016) Rational design and validation of a vanilloid-sensitive TRPV2 ion channel. Proc Natl Acad Sci U S A 113, E3657-66.
Becker EA, Yao AI, Seitzer PM, Kind T, Wang T, Eigenheer R, Shao KS, Yarov-Yarovoy V, Facciotti MT (2016) A Large and Phylogenetically Diverse Class of Type 1 Opsins Lacking a Canonical Retinal Binding Site. PLoS One 11, e0156543.
Kaur I, Yarov-Yarovoy V, Kirk LM, Plambeck KE, Barragan EV, Ontiveros ES, Díaz E (2016) Activity-Dependent Palmitoylation Controls SynDIG1 Stability, Localization, and Function. J Neurosci. 36, 7562-8.
Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Abriel H, Aldrich RW, Belardinelli L, Cannell MB, Catterall WA, Chazin WJ, Chiamvimonvat N, Deschenes I, Grandi E, Hund TJ, Izu LT, Maier LS, Maltsev VA, Marionneau C, Mohler PJ, Rajamani S, Rasmusson RL, Sobie EA, Clancy CE, Bers DM (2015) Na+ channel function, regulation, structure, trafficking and sequestration. J Physiol. 593,1347-60.
Wiek C, Schmidt EM, Roellecke K, Freund M, Nakano M, Kelly EJ, Kaisers W, Yarov-Yarovoy V, Kramm CM, Rettie AE, Hanenberg H (2015) Identification of amino acid determinants in CYP4B1 for optimal catalytic processing of 4-ipomeanol. Biochem J. 465, 103-14.
Gupta K, Zamanian M, Bae C, Milescu M, Krepkiy D, Tilley DC, Sack JT, Yarov-Yarovoy V, Kim JI, Swartz KJ (2015) Tarantula toxins use common surfaces for interacting with Kv and ASIC ion channels. eLife 4, e06774.
Yang F, Xiao X, Cheng W, Yang W, Yu P, Song Z, Yarov-Yarovoy V, Zheng J (2015) Structural mechanism underlying capsaicin binding and activation of nociceptive TRPV1 ion channel. Nat Chem Biol. 11, 518-24.
Kaur G, Pinggera A, Ortner NJ, Lieb A, Sinnegger-Brauns MJ, Yarov-Yarovoy V, Obermair GJ, Flucher BE, Striessnig J (2015) A Polybasic Plasma Membrane Binding Motif in the I-II Linker Stabilizes Voltage-Gated Cav1.2 Calcium Channel Function. J. Biol. Chem. 290, 21086-100.
Schmidt EM, Wiek C, Parkinson OT, Roellecke K, Freund M, Gombert M, Lottmann N, Steward CA, Kramm CM, Yarov-Yarovoy V, Rettie AE, and Hanenberg H (2015) Characterization of an Additional Splice Acceptor Site Introduced into CYP4B1 in Hominoidae during Evolution. PLoS One 10, e0137110.
Yang S, Yang F, Xiao X, Wei N, Hong J, Li B, Luo L, Rong M, Yarov-Yarovoy V, Zheng J, Wang K, Lai R (2015) A Pain-Inducing Centipede Toxin Targets the Heat Activation Machinery of Nociceptor TRPV1. Nat Commun. 6, 8297.
Yarov-Yarovoy V, Allen TW, and Clancy CE (2014) Computational Models for Predictive Ion Channel Pharmacology. Drug Discovery Today: Disease Models 14, 3-10.
Tilley DC, Eum KS, Fletcher-Taylor S, Austin DC, Dupré C, Patrón L, Garcia R, Lam K, Yarov-Yarovoy V, Cohen BE, and Sack JT (2014) Chemoselective tarantula toxins report voltage activation of wild-type ion channels in live cells. Proc Natl Acad Sci U S A 111, E4789-96.
Yarov-Yarovoy V.: Rosetta Structural Modeling, Zheng J, Trudeau M, (ed), (2014) Handbook of Ion Channels, CRC Press, Boca Raton.
Boiteux C, Vorobyov I, French RJ, French C, Yarov-Yarovoy V and Allen TW. (2014) Local anesthetic and anti-epileptic drug access and binding to a bacterial voltage-gated sodium channel. PNAS, 111:13057-62.
Rafizadeh S, Zhang Z, Woltz RL, Kim HJ, Myers RE, Lu L, Tuteja D, Singapuri A, Bigdeli AAZ, Harchache SB, Knowlton AA, Yarov-Yarovoy V, Yamoah EN, and Chiamvimonvat N. (2014) Functional interaction with filamin A enhances the surface membrane expression of a small-conductance Ca2+ -activated K+ (SK2) channel. PNAS, 111: 9989-9994.
Wulff H and Yarov-Yarovoy V. (2013) Channels: Sticking to nooks and crannies. Nat Chem Biol, 9: 473-4.
Timofeyev V, Myers RE, Kim HJ, Woltz RL, Sirish P, Heiserman JP, Li N, Singapuri A, Tang T, Yarov-Yarovoy V, Yamoah EN, Hammond HK, and Chiamvimonvat N. (2013) Adenylyl Cyclase Subtype–Specific Compartmentalization Differential Regulation of L-Type Ca2+ Current in Ventricular Myocytes. Circulation Res, 112: 1567-76.
Acar S, Carlson D, Budamagunta M, Yarov-Yarovoy V, Correia JJ, Niñonuevo MR, Jia W, Tao L, Leary JA, Voss J, Evans JE, Scholey JM. (2013) The Bipolar Assembly Domain of the Mitotic Motor Kinesin-5. Nat Commun 4, 1343.
Vargas E, Yarov-Yarovoy V, Khalili-Aragi F, Catterall WA, Klein ML, Tarek M, Lindahl E, Schulten K, Perozo E, Bezanilla F, and Roux B. (2012) An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations. J Gen Physiol 140, 587-94.
Khafagaa M, Bossuyt J, Mamikoniana L, Lia JC, Lee LL, Yarov-Yarovoy V, Despa S, and Bers DM. (2012) Na+/K+-ATPase E960 and Phospholemman F28 are critical for their functional interaction. PNAS 109, 20756-61.
Zhang JZ, Yarov-Yarovoy V, Scheuer T, Karbat I, Cohen L, Gordon D, Gurevitz M, and Catterall WA. (2012) Mapping the interaction site for a β-scorpion toxin in the pore module of domain III of voltage-gated sodium channels. J. Biol. Chem. 287, 30719-28.
Cui Y, Yang F, Cao X, Yarov-Yarovoy V, Wang K, Zheng J. (2012) Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations. J Gen Physiol. 139, 273-83.
Watschinger K, Fuchs JE, Yarov-Yarovoy V, Keller MA, Golderer G, Hermetter A, Werner-Felmayer G, Hulo N, Werner ER. (2012) Catalytic residues and a predicted structure of tetrahydrobiopterin-dependent alkylglycerol mono-oxygenase. Biochem J. 443, 279-86.
Yarov-Yarovoy V*, DeCaen PG*, Westenbroek, RE, Pan C-Y, Scheuer T, Baker D, and Catterall WA. (2012) Structural Basis for Gating Charge Movement in the Voltage Sensor of a Sodium Channel. PNAS 109, E93-E102.
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