Vladimir Yarov-Yarovoy, Ph.D.
4131 Tupper Hall
For more information visit the Laboratory Website.
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.
Grandi E, Sanguinetti MC, Bartos DC, Bers DM, Chen-Izu Y, Chiamvimonvat N, Colecraft HM, Delisle BP, Heijman J, Navedo MF, Noskov S, Proenza C, Vandenberg JI, Yarov-Yarovoy V (2017) Potassium channels in the heart: structure, function and regulation. Journal of Physiology 595, 2209-2228. doi: 10.1113/JP272864.
Nguyen HM, Singh V, Pressly B, Jenkins DP, Wulff H, Yarov-Yarovoy V (2017) Structural Insights into the Atomistic Mechanisms of Action of Small Molecule Inhibitors Targeting the KCa3.1 Channel Pore. Molecular Pharmacology 91, 392-402. doi: 10.1124/mol.116.108068.
Zhang P, Zawadzki RJ, Goswami M, Nguyen PT, Yarov-Yarovoy V, Burns ME, Pugh EN Jr. (2017) In vivo optophysiology reveals that G-protein activation triggers osmotic swelling and increased light scattering of rod photoreceptors. Proc Natl Acad Sci USA 114, E2937-E2946. doi: 10.1073/pnas.1620572114.
Tang C, Zhou X, Nguyen PT, Zhang Y, Hu Z, Zhang C, Yarov-Yarovoy V, DeCaen PG, Liang S, Liu Z (2017) A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel. FASEB J. 31, 3167-3178. doi: 10.1096/fj.201600882R.
Tanaka BS, Nguyen PT, Zhou EY, Yang Y, Yarov-Yarovoy V, Dib-Hajj SD, Waxman SG (2017) Gain-of-function mutation of a voltage-gated sodium channel Nav1.7 associated with peripheral pain and impaired limb development. J Biol Chem. 292, 9262-9272. doi: 10.1074/jbc.M117.778779.
Brown BM, Shim H, Zhang M, Yarov-Yarovoy V, Wulff H (2017) Structural Determinants for the Selectivity of the Positive KCa3.1 Gating Modulator 5-Methylnaphtho[2,1-d]oxazol-2-amine (SKA-121). Molecular Pharmacology [Epub ahead of print] doi: 10.1124/mol.117.109421.
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.: (2014) Rosetta Structural Modeling, Zheng J, Trudeau M, (ed), 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, (2012) Despa S, and Bers DM. 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.
Maselli RA, Fernandez JM, Arredondo J, Navarro C, Ngo M, Beeson D, Cagney O, Williams DC, Wollmann RL, Yarov-Yarovoy V, and Ferns MJ. (2012) LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. Hum Genet. 131, 1123-35.
Oganesian A, Yarov-Yarovoy V, Parks WC, and Schwinn DA. (2011) Constitutive coupling of a naturally occurring human alpha1a-adrenergic receptor genetic variant to EGFR transactivation pathway. PNAS 108, 19796-19801.
DeCaen PG, Yarov-Yarovoy V, Scheuer T, and Catterall WA. (2011) Gating Charge Interactions with the S1 Segment During Activation of a Na+ Channel Voltage Sensor. PNAS108, 18825-18830.
Wang J, Yarov-Yarovoy V, Kahn R, Gordon D, Gurevitz M, Scheuer T, and Catterall WA. (2011) Mapping the receptor site for α-scorpion toxins on Na+ channel voltage sensor. PNAS 108, 15426-15431.
Zhang JZ, Yarov-Yarovoy V, Scheuer T, Karbat I, Cohen L, Gordon D, Gurevitz M, and Catterall WA. (2011) Structure-function map of the receptor site for β-scorpion toxins in domain II of voltage-gated sodium channels. J. Biol. Chem. 286, 33641-33651.
Kisiela DI, Kramer JJ, Tchesnokova V, Aprikian P, Yarov-Yarovoy V, Clegg S, and Sokurenko EV. (2011) Allosteric catch bond properties of the FimH adhesin from Salmonella enterica serovar Typhimurium. J. Biol. Chem. 286, 38136-38147.
Kelly EJ, Nakano M, Rohatgi P, Yarov-Yarovoy V, and Rettie AE. (2011) Finding homes for orphan cytochrome P450s: CYP4V2 and CYP4F22 in disease states. Mol Interv. 11, 124-132.
Subbotina J*, Yarov-Yarovoy V*, Lees-Miller J, Durdagi S, Guo J, Duff HJ, and Noskov SY. (2010) Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations. Proteins 78, 2922-2934.
Khalili-Araghi F, Jogini V, Yarov-Yarovoy V, Tajkhorshid E, Roux B, and Schulten K. (2010) Calculation of the Gating Charge for the Kv1.2 Voltage-Activated Potassium Channel. Biophys. J. 98, 2189-2198.
Catterall WA and Yarov-Yarovoy V. (2010) Helical motion of an S4 voltage sensor revealed by gating pore currents. Channels 4, 75-77.
DeCaen PG, Yarov-Yarovoy V, Sharp EM, Scheuer T, and Catterall WA. (2009) Sequential formation of ion pairs during voltage-dependent activation of a sodium channel. PNAS 106, 22498-22503.
Lees-Miller JP, Subbotina JO, Guo J, Yarov-Yarovoy V, Noskov SY, Duff HJ. (2009) Interactions of H562 in the S5 helix with T618 and S621 in the pore helix are important determinants of hERG1 potassium channel structure and function. Biophys J.. 96, 3600-3610.
DeCaen PG, Yarov-Yarovoy V, Zhao Y, Scheuer T, and Catterall WA. (2008) Disulfide locking a sodium channel voltage sensor reveals ion pair formation during activation. PNAS 105, 15142-15147.
Pathak* MM, Yarov-Yarovoy V*, Agarwal G, Roux B, Barth P, Kohout S, Tombola F and Isacoff EY. (2007) Plunging the Shaker K+ channel to rest. Neuron 56, 124-140.
Catterall WA, Cestele S, Yarov-Yarovoy V, Yu FH, Konoki K, and Scheuer T. (2007) Voltage-gated ion channels and gating modifier toxins. Toxicon 49, 124-141.
Aprikian P, Tchesnokova V, Kidd B, Yakovenko O, Yarov-Yarovoy V, Trinchina E, Vogel V, Thomas W, Sokurenko E. (2007) Interdomain interaction in the FimH adhesin of Escherichia coli regulates the affinity to mannose. J. Biol. Chem. 282, 23437-23446.
Yarov-Yarovoy V, Baker D, and Catterall WA. (2006) Voltage Sensor Conformations in the Open and Closed States in Rosetta Structural Models of K+ Channels. PNAS 103, 7292-7297.
Yarov-Yarovoy V*, Schonbrun J*, and Baker D. (2006) Multipass Membrane Protein Structure Prediction Using Rosetta. Proteins 62, 1010-1025.
Hulme JT, Yarov-Yarovoy V, Lin TWC, Scheuer T, and Catterall WA. (2006) Autoinhibitory Control of the Cav1.2 Channel by its Proteolytically Processed Distal C-terminal Domain. J. Physiol;. 103(44), 16574-16579.
Cestèle S, Yarov-Yarovoy V, Qu Y, Sampieri F, Scheuer T, and Catterall WA. (2006) Structure and Function of the Voltage Sensor of Sodium Channels Probed by a β-Scorpion Toxin. J. Biol. Chem. 281, 21332-21344.
Yu F, Yarov-Yarovoy V, Gutman GA, and Catterall WA. (2005) Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol Rev. 57, 387-395.
Zhao Y, Yarov-Yarovoy V, Scheuer T, and Catterall WA. (2004) The Gating Hinge of a Voltage-Gated Sodium Channel: A Molecular Switch Controlling Electrical Signaling. Neuron, 41(6), 859-865
- University of Washington Royalty Research Fund Award, University of Washington
- National Institutes of Health Research Career Development Award
- Biophysical Society Graduate Student Award
- 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
- Biophysical Society
- Protein Society
- National Institutes of Health
- University of Washington