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.
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.
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. PNAS 108, 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.
Liu G, Yarov-Yarovoy V, Nobbs M, Clare JJ, Scheuer T, and Catterall WA (2003) Differential Interactions of Lamotrigine and Related Drugs with Transmembrane Segment IVS6 of Voltage-Gated Sodium Channels. Neuropharmacology, 44, 413-422.
Yarov-Yarovoy V, McPhee JC, Idsvoog D, Pate C, Scheuer T, and Catterall WA (2002) Role of Amino Acid Residues in Transmembrane Segments IS6 and IIS6 of the Na+ Channel a Subunit in Voltage-dependent Gating and Drug Block. J. Biol. Chem., 277, 35393-35401.
Yarov-Yarovoy Y, Brown J, Sharp E, Clare JJ, Scheuer T, and Catterall WA (2001) Molecular Determinants of Voltage-dependent Gating and Binding of Pore-blocking Drugs in Transmembrane Segment IIIS6 of the Na+ a Subunit. J. Biol. Chem., 276, 20-27.
Jaburek M, Yarov‑Yarovoy V, Paucek P, and Garlid KD (1998) State‑dependent Inhibition of the Mitochondrial KATP Channel by Glyburide and 5‑Hydroxydecanoate. J. Biol. Chem., 273, 13578‑13582.
Garlid KD, Paucek P, Yarov‑Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, and Grover GJ (1997) Cardioprotective Effect of Diazoxide and its Interaction with Mitochondrial ATP‑Sensitive Potassium Channels: Possible Mechanism of Cardioprotection. Circulation Res., 81, 1072‑1082.
Yarov‑Yarovoy V, Paucek P, Jaburek M, and Garlid KD (1997) The Nucleotide Regulatory Sites on the Mitochondrial KATP Channel Face the Cytosol. Biochim. Biophys. Acta., 1321, 128‑136.
Mironova GD, Skarga YY, Grigoriev SM, Yarov‑Yarovoy V, Alexandrov AV, and Kolomytkin OV (1996) The ATP‑Dependent Potassium Channel from Rat Liver Mitochondria. 1. Isolation, Purification, and Reconstitution in a Bilayer Lipid Membrane. Membr. Cell Biol., 10, 429‑ 437.
Paucek P, Yarov‑Yarovoy V, Sun X, and Garlid KD (1996) Inhibition of the Mitochondrial KATP Channel by Long Chain Acyl‑CoA Esters and Activation by Guanine Nucleotides. J. Biol. Chem., 271, 32084‑32088.
Garlid KD, Paucek P, Yarov‑Yarovoy V, Sun X, and Schindler P (1996) The Mitochondrial KATP Channel as a Receptor for Potassium Channel Openers. J. Biol. Chem., 271, 8796‑8799.